Non-sedating dexmedetomidine treatment regimens

ABSTRACT

Disclosed herein are methods of administering relatively high doses of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject, without also inducing significant sedation. The disclosed methods are particularly suitable for the treatment of agitation, especially when associated with neurodegenerative and/or neuropsychiatric diseases such as schizophrenia, bipolar illness such as bipolar disorder or mania, dementia, depression, or delirium.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 17/993,422, filed Nov. 23, 2022, which is acontinuation application of U.S. patent application Ser. No. 17/628,021,filed Jan. 18, 2022, which is a U.S. national stage of InternationalPatent Application No. PCT/US2020/042618, filed Jul. 17, 2020, whichclaims the benefit of priority under 35 U.S.C. 119 (e) to U.S.Provisional Patent Application No. 62/876,371 filed Jul. 19, 2019; U.S.Provisional Patent Application No. 62/877,056 filed Jul. 22, 2019; U.S.Provisional Patent Application No. 62/963,769 filed Jan. 21, 2020; U.S.Provisional Patent Application No. 62/970,411 filed Feb. 5, 2020; U.S.Provisional Patent Application No. 62/977,554 filed Feb. 17, 2020; U.S.Provisional Patent Application No. 63/037,759 filed Jun. 11, 2020; andU.S. Provisional Patent Application No. 62/943,022 filed Dec. 3, 2019;the disclosures of each of which are incorporated herein by reference intheir entireties.

FIELD

Disclosed herein are methods of treating a human subject having acondition (e.g. agitation) which can be improved using an alpha-2adrenergic receptor agonist. The methods comprise administeringdexmedetomidine or a pharmaceutically acceptable salt thereof at asuitable dose, and via an appropriate route of administration, toachieve a plasma concentration profile that provides a rapid improvementto the subject's condition without also inducing significant sedation.The administration regimens are also selected to provide maximumtherapeutic benefit to the subject, without incurring any significantside effects, such as undesirable cardiovascular events. Suitable routesof administration include sublingual, buccal, oral, intranasal andparenteral. The disclosed methods are particularly suitable for thetreatment of agitation or signs of agitation, especially when associatedwith neurodegenerative and/or neuropsychiatric diseases such asschizophrenia, a bipolar illness such as bipolar disorder or mania,dementia, depression and delirium.

BACKGROUND

On Dec. 17, 1999, the U.S. Food and Drug Administration approved adexmedetomidine product, PRECEDEX®, formulated as an intravenoussolution for continuous infusion, and indicated as a sedative agent forinitially intubated and mechanically ventilated patients duringtreatment in an intensive care setting. PRECEDEX® was later approved asa sedative agent for non-intubated patients prior to and/or duringsurgical and other procedures.

Dexmedetomidine has also been administered intravenously and via otherroutes to treat a range of conditions, often peri- or post-surgery,including the treatment of pain, anxiety, delirium, withdrawal symptoms,sleep disorders and agitation. However, administration ofdexmedetomidine in an appropriate dosage form to provide effective,rapid, relief for the subject without also causing significant sedationis a challenging task. The utilization of dexmedetomidine has also beenlimited in clinical practice due to its common side effects, such ashypotension and bradycardia. For example, significant cardiovascularside-effects have occurred at therapeutic doses following administrationof dexmedetomidine hydrochloride via a sublingual spray or tablets, orintravenously. Thus, a continuing, unmet need exists for an effectivedexmedetomidine product which does not cause significant sedation, anddesirably is effective without also producing significant adverseeffects, such as cardiovascular events. The unmet need is particularlyacute for non-addictive medicines that can effectively treat agitationor signs of agitation without also producing the aforementioned adverseeffects and sedation.

The inventors of the present application have surprisingly found thatrelatively high doses of dexmedetomidine hydrochloride can bewell-tolerated by human subjects without inducing accompanyingsignificant sedation, when administered via particular treatmentregimens. For example, a dose of at least 180 μg of dexmedetomidinehydrochloride, administered sublingually, is shown herein, according tothe present disclosure, to be effective to treat agitation withoutinducing significant sedation, while being safe and well tolerated.Surprisingly, doses of 120 μgand 180 μg of dexmedetomidinehydrochloride, administered sublingually, such as via a film, have alsobeen found to produce pharmacokinetic profiles that are superior toPRECEDEX®, leading to fewer cardiovascular adverse events. Further, theinventors have found that subjects respond well when dexmedetomidinehydrochloride is administered at doses of at least 180 μg, and show asignificant improvement in agitation as early as 45 minutes followingadministration, with the calming effect maintained for a prolongedperiod of time, e.g. up to at least 24 hours.

SUMMARY

In some embodiments, the present disclosure provides methods of treatingagitation or signs of agitation in a human subject with schizophrenia orbipolar disorder (e.g. bipolar I disorder), without also inducingsignificant sedation, comprising administering dexmedetomidine or apharmaceutically acceptable salt thereof at a dose resulting in a meantotal exposure of dexmedetomidine, as measured by plasma AUC from T0 toT∞, of about 3800 ng*h/L.

In some embodiments, the present disclosure provides methods of treatingagitation or signs of agitation in a human subject with schizophrenia orbipolar disorder, without also inducing significant sedation, comprisingadministering dexmedetomidine or a pharmaceutically acceptable saltthereof at a dose resulting in a mean total exposure of dexmedetomidine,as measured by plasma AUC from T0 to T∞, of about 1800 ng*h/L.

In some embodiments, the present disclosure provides methods of treatingagitation or signs of agitation in a human subject with schizophrenia orbipolar disorder, without also inducing significant sedation, comprisingadministering dexmedetomidine or a pharmaceutically acceptable saltthereof at a dose resulting in a total exposure of dexmedetomidine, asmeasured by plasma AUC from T0 to T∞, from about 600 ng*h/L to about12600 ng*h/L.

In some embodiments, the present disclosure provides methods of treatingagitation or signs of agitation in a human subject with schizophrenia orbipolar disorder, without also inducing significant sedation, comprisingadministering dexmedetomidine or a pharmaceutically acceptable saltthereof at a dose resulting in a total exposure of dexmedetomidine, asmeasured by plasma AUC from T0 to T∞, from about 590 ng*h/L to about8750 ng*h/L.

The present disclosure also provides methods of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingadministering about 180 μg of dexmedetomidine or a pharmaceuticallyacceptable salt thereof as a single dose. In another embodiment, anadditional dose of 90 μg or 60 μg may be taken after 2 hours of firstdose.

The present disclosure further provides methods of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingadministering about 120 μg of dexmedetomidine or a pharmaceuticallyacceptable salt thereof as a single dose. In another embodiment, anadditional dose of 90 μg or 60 μg may be taken after 2 hours of firstdose.

In some embodiments, the present disclosure provides administering about180 μg of dexmedetomidine hydrochloride sublingually as a single dose toa human subject, wherein said administration results in substantiallylower systemic exposure levels of dexmedetomidine than administration ofPRECEDEX® at its highest approved dose, as measured by comparative Cmaxand AUC values.

In some embodiments, the present disclosure provides administering about120 μg of dexmedetomidine hydrochloride sublingually as a single dose toa human subject, wherein said administration results in substantiallylower systemic exposure levels of dexmedetomidine than administration ofPRECEDEX® at its highest approved dose, as measured by comparative Cmaxand AUC values.

The lower systemic exposure reduces the risk of reduced blood pressureand/or respiratory depression commonly encountered when administratingeffective amounts of PRECEDEX®.

In some embodiments, the administration of about 180 μg ofdexmedetomidine hydrochloride sublingually as a single dose providesabout a three-fold reduction in the Cmax value compared toadministration of PRECEDEX®. In some embodiments, the aforementionedsublingual administration provides about a 7.5-fold reduction in the AUCvalue compared to administration of PRECEDEX®. In one particularembodiment, administering a sublingual film to a human subjectcomprising about 180 μg of dexmedetomidine hydrochloride provides abouta three-fold reduction in the Cmax value and about a 7.5-fold reductionin the AUC value compared to administration of PRECEDEX®.

In some embodiments, the present disclosure provides the administrationof about 180 of dexmedetomidine or a pharmaceutically acceptable saltthereof sublingually or buccally to a human subject, wherein saidadministration results in mean plasma absorption levels ofdexmedetomidine from about 80% to about 125% of the following values:Cmax of about 400 ng/L and AUC from T0 to T∞ of about 2900 ng*h/L.

In some embodiments, the present disclosure provides the administrationof about 120 of dexmedetomidine or a pharmaceutically acceptable saltthereof sublingually or buccally to a human subject, wherein saidadministration results in mean plasma absorption levels ofdexmedetomidine from about 80% to about 125% of the following values:Cmax of about 220 ng/L and AUC from T0 to T∞ of about 1420 ng*h/L.

In some embodiments, the present disclosure provides the administrationof about 180 of dexmedetomidine or a pharmaceutically acceptable saltthereof sublingually or buccally to a human subject, wherein saidadministration results in plasma absorption levels of dexmedetomidinefrom about 80% to about 125% of the following values: Cmax from about100 ng/L to about 800 ng/L and AUC from T0 to T∞ of about 600 hr*ng/Labout 9500 hr*ng/L.

In some embodiments, the present disclosure provides the administrationof about 120 μg of dexmedetomidine or a pharmaceutically acceptable saltthereof sublingually or buccally to a human subject, wherein saidadministration results in plasma absorption levels of dexmedetomidinefrom about 80% to about 125% of the following values: Cmax from about110 ng/L to about 400 ng/L and AUC from T0 to T∞ of about 590 hr*ng/Labout 4400 hr *ng/L.

The present disclosure also provides methods of treating agitation orsigns of agitation in a human subject with dementia, without alsoinducing significant sedation, comprising administering about 30 μg toabout 180 μg of dexmedetomidine or a pharmaceutically acceptable saltthereof. In some embodiments, the disclosure provides methods oftreating agitation or signs of agitation in a human subject withdementia, without also inducing significant sedation, comprisingadministering 30 μg, 60 μg or 90 μg of dexmedetomidine or apharmaceutically acceptable salt thereof as a single dose in a day. Insome embodiments, the disclosure provides methods of treating agitationor signs of agitation in a human subject with dementia, without alsoinducing significant sedation, comprising oromucosally administering anunit dose containing about 30 μg to about 90 μg of dexmedetomidine or apharmaceutically acceptable salt thereof one to six times a day at aninterval of at least 2 hours (e.g. 2, 4, 6, 8, or 12 hours) in the eventof persistent or recurrent agitation. In some embodiments,dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g.hydrochloride) is administered oromucosally (e.g. sublingually orbuccally) as a film.

The present disclosure provides a method of reducing a period of opioidwithdrawal in a human subject in need thereof, comprising administeringto said subject dexmedetomidine or a pharmaceutically acceptable saltthereof twice daily, wherein the period of withdrawal is up to 14 days.In some embodiments, the period of withdrawal may be 13 days, 12 days,11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3days. In another embodiment, the human subject is an adult (at least 18years old). In some embodiments, dexmedetomidine or a pharmaceuticallyacceptable salt is administered oromucosally (i.e. sublingually,buccally), orally, intranasally or parenterally. In some embodiments,dexmedetomidine or a pharmaceutically acceptable salt (e.g.hydrochloride) is administered sublingually as a film. In someembodiments, dexmedetomidine or a pharmaceutically acceptable saltthereof is oromucosally administered at a dose range of about 30 μg toabout 200 μg. In specific embodiment, dexmedetomidine or apharmaceutically acceptable salt thereof is oromucosally administered ata unit dose containing about 30 μg, about 60 μg, about 90 μg, 120 μg or180 μg twice daily. In some embodiments, the opioid may be selected fromthe group consisting of, but are not limited to fentanyl, morphine,codeine, heroin, oxycodone, hydrocodone, alfentanil carfentanil,tramadol, hydromorphone, buprenorphine, naloxone, naltrexone,remifentanil butorphanol, meperidine, methadone, dextropropoxyphene(propoxyphene) thebaine, sufentanil or pentazocine.

The present disclosure also provides methods of managing or treatingagitation in delirium in subjects, without also inducing significantsedation, comprising administering about 20 μg to about 240 μg ofdexmedetomidine or a pharmaceutically acceptable salt thereof. In someembodiments, the subject is hospitalized. In some embodiments, thesubject is hospitalized in the intensive care unit. In some embodiments,dexmedetomidine or a pharmaceutically acceptable salt thereof isoromucosally administered at a unit dose containing about 20 μg or 60 μgas a single dose. In some embodiments, each dosage unit may beadministered one to four times at an appropriate dosing interval (fore.g. of at least 0.5 hours) to produce a desired effect; for example, 20μg unit is administered four times at a dosing interval of 0.5 hourswithin 6 hours of first dose to produce the effect of a 80 μg dose or 60μg unit is administered four times at a dosing interval of 0.5 hourswithin 6 hours of first dose to produce the effect of 240 μg dose. Insome embodiments, dexmedetomidine or a pharmaceutically acceptable saltthereof is administered oromucosally (e.g. sublingually or buccally) asa film.

The present disclosure also provides a method of treating agitationassociated with schizophrenia or bipolar disorder, comprisingadministering a unit dose composition comprising about 120 μg ofdexmedetomidine (e.g. dexmedetomidine hydrochloride) or apharmaceutically acceptable salt thereof to a human patient. Forexample, in some embodiments, the patient has schizophrenia, in someembodiments, the patient has bipolar disorder (E.g. bipolar I disorder,and in some embodiments, the patient has both schizophrenia and bipolardisorder (e.g. bipolar I disorder).

In some embodiments, the present disclosure provides a method oftreating agitation associated with schizophrenia or bipolar disorder,comprising administering a unit dose composition comprising about 180 μgof dexmedetomidine (e.g. dexmedetomidine hydrochloride) or apharmaceutically acceptable salt thereof to a human patient. Forexample, in some embodiments, the patient has schizophrenia, in someembodiments, the patient has bipolar disorder (E.g. bipolar I disorder,and in some embodiments, the patient has both schizophrenia and bipolardisorder (e.g. bipolar I disorder).

The present disclosure also provides a method of treating agitationassociated with schizophrenia or bipolar disorder, comprisingadministering a unit dose composition comprising about 120 to about 180μg of dexmedetomidine (e.g. dexmedetomidine hydrochloride) or apharmaceutically acceptable salt thereof to a human patient. Forexample, in some embodiments, the patient has schizophrenia, in someembodiments, the patient has bipolar disorder (E.g. bipolar I disorder,and in some embodiments, the patient has both schizophrenia and bipolardisorder (e.g. bipolar I disorder).

The present disclosure also provides methods of treating or amelioratingopioid withdrawal symptoms, comprising administering a compositioncomprising dexmedetomidine or a pharmaceutically acceptable salt thereof(e.g. dexmedetomidine hydrochloride) to a human patient in need thereof,wherein the patient is at least 18 years and wherein the period ofwithdrawal is up to 14 days. “Opioid withdrawal” refers to a variety ofsigns and complaints appearing with the abrupt removal of, or a rapiddecrease in the regular dosage of opioids. Physical manifestations mayinclude sweating, nausea, yawning, chills, diarrhea, papillary dilation,piloerection, tachycardia, increased blood pressure, hypersensitivity topain, stomach cramps, and muscle cramps. Psychological manifestations ofopioid withdrawal observed may include agitation, dysphoria,restlessness, irritability, anxiety, and depression. In someembodiments, the opioid withdrawal symptom is agitation. Onset oftenbegins within 6-24 hours from last opioid use. In some embodiments,treating or ameliorating opioid withdrawal refers to the treatment orlessening of one or more of the aforementioned symptoms. The treating orameliorating may be measured by a variety of well-known means in theart, including but not limited to, the Clinical Opiate Withdrawal Scale(COWS) and/or Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop)score.

The present disclosure also provides a pharmaceutical compositioncomprising from about 20 μg to about 240 μg dexmedetomidine or apharmaceutically acceptable salt thereof (e.g. dexmedetomidinehydrochloride). In some embodiments, the dose of dexmedetomidine isabout 120 μg. In some embodiments, the dose of dexmedetomidine is about180 μg.

The present disclosure also provides methods of achieving a ≥40%reduction in agitation, within 2 hours of administering a compositioncomprising dexmedetomidine or a pharmaceutically acceptable saltthereof, as measured by the PEC scale. In some embodiments, theagitation is reduced within about 20 minutes to about 1 hour; forexample, within about 20 minutes, about 30 minutes, or about 40 minutes.In some embodiments, the reduction in agitation ≥40%, ≥50%, ≥60%, ≥70%,≥80%, ≥90%, or ≥100%. In some embodiments, the reduction in agitation ismaintained for greater than about 2 hours. For example, the reduction inagitation is maintained for about 2 hours, about 3 hours, about 4 hours,about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours,about 23 hours, or about 24 hours. In some embodiments, the compositioncomprises about 120 μg of dexmedetomidine. In some embodiments, thecomposition comprises about 180 μg of dexmedetomidine. In someembodiments, the patient has schizophrenia. In some embodiments, thepatient has bipolar disorder.

The present disclosure also provides a method of achieving a PEC scorereduction in agitation for a sustained period of time in a subject withbipolar disorder or schizophrenia comprising administering to thesubject a pharmaceutical composition comprising dexmedetomidine or apharmaceutically acceptable salt thereof at a dose of about 120 mcg toabout 180 mcg wherein the PEC score reduction is about −8 to about −10and wherein the sustained period is about 2 hours to about 6 hours. Insome embodiments, the composition comprises dexmedetomidinehydrochloride. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof is administered at a dose ofabout 120 mcg. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof is administered at a dose ofabout 180 mcg. In some embodiments, the sustained period is about 2hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours,about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours,about 21 hours, about 22 hours, about 23 hours, or about 24 hours. Insome embodiments, the PEC score reduction is about −8, about −9, orabout −10.

The present disclosure also provides a method of achieving an ACES scoreimprovement for a sustained period of time in a subject with bipolardisorder or schizophrenia comprising administering to the subject apharmaceutical composition comprising dexmedetomidine or apharmaceutically acceptable salt thereof at a dose of about 120 mcg toabout 180 mcg wherein the ACES score is improved to about 3 to about 4and wherein the sustained period is about 2 hours to about 6 hours. Insome embodiments, the composition comprises dexmedetomidinehydrochloride. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof is administered at a dose ofabout 120 mcg. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof is administered at a dose ofabout 180 mcg. In some embodiments, the sustained period is about 2hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours,about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours,about 21 hours, about 22 hours, about 23 hours, or about 24 hours. Insome embodiments, the ACES score is about 4.

The present disclosure also provides a method of achieving an CGI-Iscore improvement for a sustained period of time in a subject withbipolar disorder or schizophrenia comprising administering to thesubject a pharmaceutical composition comprising dexmedetomidine or apharmaceutically acceptable salt thereof at a dose of about 120 mcg toabout 180 mcg wherein the CGI-I score is improved to about 1 (very muchimproved) or about a 2 (much improved) and wherein the sustained periodis about 2 hours to about 6 hours. In some embodiments, the compositioncomprises dexmedetomidine hydrochloride. In some embodiments,dexmedetomidine or a pharmaceutically acceptable salt thereof isadministered at a dose of about 120 mcg. In some embodiments,dexmedetomidine or a pharmaceutically acceptable salt thereof isadministered at a dose of about 180 mcg. In some embodiments, thesustained period is about 2 hours, about 3 hours, about 4 hours, about 5hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about10 hours, about 11 hours, about 12 hours, about 13 hours, about 14hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours,about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23hours, or about 24 hours. In some embodiments, the CGI-I score is about1.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 : depicts the mean change from baseline in PEC total score inschizophrenic patients (Intent to treat Population) treated with asublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg,120 μg and 180 μg) versus a placebo group. The preparation ofdexmedetomidine hydrochloride sublingual film (60 μg) is exemplified inExample 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120μg and 180 μg) are exemplified in Example 2.

FIG. 2 : depicts the percent of responders in PEC total score over timein schizophrenic patients (Intent to treat Population) treated with asublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg,120 μg and 180 μg) versus a placebo group. The preparation ofdexmedetomidine hydrochloride sublingual film (60 μg) is exemplified inExample 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120μg and 180 μg) are exemplified in Example 2.

FIG. 3 : depicts resolution of agitation as measured by achieving anACES Score of at least 4 over time in schizophrenic patients (Intent totreat Population) treated with a sublingual film containingdexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus aplacebo group. The error bars in the figure represent “standard error”.The preparation of dexmedetomidine hydrochloride sublingual films (60μg) is exemplified in Example 1 and dexmedetomidine hydrochloridesublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example2.

FIG. 4 : depicts percent of responders in CGI-I Score over time inschizophrenic patients (Intent to treat Population) treated with asublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg,120 μg and 180 μg) versus a placebo group. The error bars in the figurerepresent “standard error”. The preparation of dexmedetomidinehydrochloride sublingual film (60 μg) is exemplified in Example 1 anddexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180μg) are exemplified in Example 2.

FIG. 5A: depicts mean dexmedetomidine plasma concentration vs. nominaltime sorted by dose and redose (Semilog Scale) in schizophrenic patients(Pharmacokinetic Population) treated with a sublingual film containingdexmedetomidine hydrochloride (20 μg, 20 μg (redose), 60 μg, 80 μg, 120μg and 180 μg) versus a placebo group. The preparation ofdexmedetomidine hydrochloride sublingual films (20 μg and 60 μg) areexemplified in Example 1 and dexmedetomidine hydrochloride sublingualfilms (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 5B: depicts mean dexmedetomidine plasma concentration vs. nominaltime sorted by dose and redose (Linear Scale) in schizophrenic patients(Pharmacokinetic Population) treated with a sublingual film containingdexmedetomidine hydrochloride (20 μg, 20 μg (redose), 60 μg, 80 μg, 120μg and 180 μg) versus a placebo group. The preparation ofdexmedetomidine hydrochloride sublingual films (20 μg and 60 μg) areexemplified in Example 1 and dexmedetomidine hydrochloride sublingualfilms (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 6A: depicts mean values for resting systolic blood pressure (SBP)over time in schizophrenic patients (Safety Population) treated with asublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg,120 μg and 180 μg) versus a placebo group. The preparation ofdexmedetomidine hydrochloride sublingual film (60 μg) is exemplified inExample 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120μg and 180 μg) are exemplified in Example 2.

FIG. 6B: depicts mean values for resting diastolic blood pressure (DBP)over time in schizophrenic patients (Safety Population) treated with asublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg,120 μg and 180 μg) versus a placebo group. The preparation ofdexmedetomidine hydrochloride sublingual film (60 μg) is exemplified inExample 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120μg and 180 μg) are exemplified in Example 2.

FIG. 6C: depicts mean values for resting heart rate (HR) over time inschizophrenic patients (Safety Population) treated with a sublingualfilm containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and180 μg) versus a placebo group. The preparation of dexmedetomidinehydrochloride sublingual film (60 μg) is exemplified in Example 1 anddexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180μg) are exemplified in Example 2.

FIG. 7A: depicts mean change from baseline for resting systolic bloodpressure (SBP) over time in schizophrenic patients (Safety Population)treated with a sublingual film containing dexmedetomidine hydrochloride(60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. Thepreparation of dexmedetomidine hydrochloride sublingual film (60 μg) isexemplified in Example 1 and dexmedetomidine hydrochloride sublingualfilms (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 7B: depicts mean change from baseline for resting diastolic bloodpressure (DBP) over time in schizophrenic patients (Safety Population)treated with a sublingual film containing dexmedetomidine hydrochloride(60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. Thepreparation of dexmedetomidine hydrochloride sublingual film (60 μg) isexemplified in Example 1 and dexmedetomidine hydrochloride sublingualfilms (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 7C: depicts mean change from baseline for resting heart rate (HR)over time in schizophrenic patients (Safety Population) treated with asublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg,120 μg and 180 μg) versus a placebo group. The preparation ofdexmedetomidine hydrochloride sublingual film (60 μg) is exemplified inExample 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120μg and 180 μg) are exemplified in Example 2.

FIG. 8 : shows the mean dexmedetomidine plasma log concentration vs.time for dose levels 10 μg, 20 μg and 40 μg of dexmedetomidinesublingual film (Semi-log scale). Error bars represent 1 standarddeviation.

FIG. 9A: depicts individual dexmedetomidine concentration-time profilesfor all subjects by dose after administration of dexmedetomidinesublingual film (10 μg) Semi-log Scale. Dexmedetomidine sublingual filmis exemplified in Example 1.

FIG. 9B: depicts individual dexmedetomidine concentration-time profilesfor all subjects by dose after administration of dexmedetomidinesublingual film (20 μg) Semi-log Scale. Dexmedetomidine sublingual filmis exemplified in Example 1.

FIG. 9C: depicts individual dexmedetomidine concentration-time profilesfor all subjects by dose after administration of dexmedetomidinesublingual film (40 μg) Semi-log Scale. The preparation ofDexmedetomidine sublingual film is exemplified in Example 1.

FIGS. 10A-10B: depict mean VAS/S score vs. nominal time afteradministration of dexmedetomidine sublingual film (10 μg, 20 μg, 40 μg)and placebo. Dexmedetomidine sublingual film (10 μg and 20 μg) and thepreparation of dexmedetomidine sublingual film (40 μg) are exemplifiedin Example 1.

FIGS. 11A-11B: depict standing systolic BP vs nominal time afteradministration of dexmedetomidine sublingual film (10 μg, 20 μg, 40 μg)and placebo. Dexmedetomidine sublingual film (10 μg and 20 μg) and thepreparation of dexmedetomidine sublingual film (40 μg) are exemplifiedin Example 1.

FIGS. 12A-12B: depict supine systolic BP. vs nominal time afteradministration of dexmedetomidine sublingual film 10 μg, 20 μg and 40 μgand placebo. Dexmedetomidine sublingual film (10 μg and 20 μg) and thepreparation of dexmedetomidine sublingual film (40 μg) are exemplifiedin Example 1.

FIGS. 13A-13B: depict standing diastolic BP vs nominal time afteradministration of dexmedetomidine sublingual film 10 μg, 20 μg and 40 μgand placebo. Dexmedetomidine sublingual film (10 μg and 20 μg) and thepreparation of dexmedetomidine sublingual film (40 μg) are exemplifiedin Example 1.

FIGS. 14A-14B: depict supine diastolic BP vs nominal time afteradministration of dexmedetomidine sublingual film 10 μg, 20 μg and 40 μgand placebo. Dexmedetomidine sublingual film (10 μg and 20 μg) and thepreparation of dexmedetomidine sublingual film (40 μg) are exemplifiedin Example 1.

FIGS. 15A-15B: depict pulse rate vs nominal time after administration ofdexmedetomidine sublingual film 10 μg, 20 μg and 40 μg and placebo.Dexmedetomidine sublingual film (10 μg and 20 μg) and the preparation ofdexmedetomidine sublingual film (40 μg) are exemplified in Example 1.

FIG. 16 : depicts the percentage of schizophrenic patients achievingRASS −1 in the treatment arm (IV dexmedetomidine hydrochloride treatedgroup) versus placebo group.

FIG. 17 : depicts the mean drop in PEC score with time in schizophrenicpatients in the treatment arm (IV dexmedetomidine hydrochloride treatedgroup) versus placebo group.

FIG. 18 : depicts the maximum doses of IV dexmedetomidine hydrochloridereceived by schizophrenic patients for the treatment of agitation.

FIG. 19 : depicts the total intravenous dose of dexmedetomidinehydrochloride received by schizophrenic patients for the treatment ofagitation.

FIG. 20 : depicts the mean plasma concentration (pg/ml) vs actual timein schizophrenic patients treated with dexmedetomidine hydrochloride.

FIG. 21A: depicts change in PEC score from baseline in schizophreniapatients until 2 hours post-dose of 120 μg and 180 μg dexmedetomidinesublingual thin film (as exemplified in example 2) compared to placebo.

FIG. 21B: depicts change in PEC score from baseline in schizophreniapatients until 6 hours post-dose of 120 μg and 180 μg dexmedetomidinesublingual film (as exemplified in example 2) compared to placebo.

FIG. 22 : depicts calming improvement in schizophrenia patients at 2hours and 4 hours following administration of 120 μg (middle bar) and180 μg dexmedetomidine (right bar) sublingual film (as exemplified inexample 2) compared to placebo (left bar), as measured by Agitation andCalmness Evaluation Scale (ACES).

FIG. 23 : depicts percent response in schizophrenia patients at 30minutes, 60 minutes, 120 minutes and 240 minutes followingadministration of 120 μg (middle bar) and 180 dexmedetomidine (rightbar) sublingual film (as exemplified in example 2) compared to placebo(left bar), as measured by Clinical Global Impression-Improvement (CGI).

FIG. 24A: depicts change in PEC score from baseline in bipolar patientsuntil 2 hours post-dose of 120 μg and 180 μg dexmedetomidine sublingualfilm (as exemplified in example 2) compared to placebo.

FIG. 24B: depicts change in PEC score from baseline in bipolar patientsuntil 6 hours post-dose of 120 μg and 180 μg dexmedetomidine sublingualfilm (as exemplified in example 2) compared to placebo.

FIG. 25 depicts calming improvement in bipolar patients at 2 hours and 4hours following administration of 120 μg (middle bar) and 180 μgdexmedetomidine (right bar) sublingual film (as exemplified in example2) compared to placebo (left bar), as measured by Agitation and CalmnessEvaluation Scale (ACES).

FIG. 26 depicts percent response in bipolar patients at 30 minutes, 60minutes, 120 minutes and 240 minutes following administration of 120 μg(middle bar) and 180 μg dexmedetomidine (right bar) sublingual film (asexemplified in example 2) compared to placebo (left bar), as measured byClinical Global Impression-Improvement (CGI).

DETAILED DESCRIPTION Abbreviations

ACES: Agitation-Calmness Evaluation Scale;

AD: Alzheimer disease;

AE: Adverse event;

AUC: Area under the curve;

AUClast: area under the curve, calculated to the last observable timepoint;

AUC0-Inf: Area under the plasma concentration-time curve from time ofadministration to infinity

BID: twice a day;

BMI: Body mass index;

CGI-I: Clinical Global Impression-Improvement

CGI-S: Clinical Global Impression-Severity

Cmax: maximum plasma concentration;

COWS: Clinical Opiate Withdrawal Scale;

CMAI: Cohen Mansfield Agitation Inventory

CMC: Carboxy methylcellulose

C-SSRS: Columbia Suicide Severity Rating Scale

CT: Computed tomography;

CTCAE: Common Terminology Criteria for Adverse Events;

DBP: Diastolic Blood Pressure

Dex or DEX: Dexmedetomidine

DLB: Dementia with Lewy bodies;

DLT: Dose Limiting Toxicity;

DSM: Diagnostic and Statistical Manual of Mental Disorders;

DT: Disintegration time;

ECG: Electrocardiogram;

FTD: Fronto temporal disease;

HPC: Hydroxypropyl cellulose;

HPMC: Hydroxyl propyl methyl cellulose

HR: Heart rate

ICH: International Conference on Harmonisation;

ICU—Intensive care unit;

IUD: intrauterine device

IPD: In-patient Departments;

ITT: Intent to treat Population

LAR: Legally authorized representative;

LSM: Least square mean

LS: Least square;

MedDRA: Medical Dictionary for Regulatory Activities;

MMRM: Mixed model repeated measures;

MMSE: Mini-Mental State Examination;

MRI: Magnetic resonance imaging;

MW: Molecular weight;

mm: Millimeter;

mcg: microgram;

mg: Milligrams;

μg: microgram;

ml: milliliter;

mmHG: millimeters of mercury;

msec: millisecond;

ng: nanogram;

OPD: Out-Patient Department;

PANSS: Positive and Negative Syndrome Scale;

PAS: Pittsburgh Agitation Scale;

PCRS: Placebo-Control Reminder Script;

PEC: PANSS Excitement Component;

PEO: Polyethylene oxide;

PD: Pharmacodynamic;

PK: Pharmacokinetics

PVA: Polyvinyl alcohol;

QTcF: QT interval corrected for heart rate using Fridericia's formula;

QID: Quater in die

RASS: Richmond Agitation Sedation Scale;

SAE: Serious adverse event;

SOWS-Gossop: Short Opiate Withdrawal Scale of Gossop;

SAP: Statistical Analysis Plan;

SBP: Systolic Blood Pressure

SD=standard deviation;

SE=standard error

SL: Sublingual;

T_(1/2): Elimination half-life;

TEAE: treatment emergent adverse event;

Tmax: Time of maximum plasma concentration;

Wt %: Weight percentage

ULN: upper limit of normal

VAS: Visual Analog Scale;

YMRS: Young Mania Rating Scale

Definitions

As used herein, “about” means plus or minus 10% of the indicatednumerical value.

The terms “formulation” and “composition” are used interchangeably,except where otherwise clearly intended to have different meanings.

Throughout the present specification, numerical ranges are provided forcertain quantities. It is to be understood that these ranges compriseall subranges therein. Thus, the range “from 50 to 80” includes allpossible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70,etc.). Furthermore, all values within a given range may be an endpointfor the range encompassed thereby (e.g., the range 50-80 includes theranges with endpoints such as 55-80, 50-75, etc.).

The term “a” or “an” refers to one or more of that entity. As such, theterms “a” (or “an”), “one or more” and “at least one” are usedinterchangeably herein. In addition, reference to w,g, “an agent” by theindefinite article “a” or “an” does not exclude the possibility thatmore than one of the agents are present, unless the context clearlyrequires that there is one and only one of the agents.

As used herein, the verb “comprise” as is used in this description andin the claims and its conjugations are used in its non-limiting sense tomean that items following the word are included, but items notspecifically mentioned are not excluded. The present invention maysuitably “comprise”, “consist of”, or “consist essentially of”, thesteps, elements, and/or reagents described in the claims.

The term “pharmaceutically acceptable carrier” refers to apharmacologically inert substance to be used as a carrier. As usedherein, the phrase “carrier” and “excipients” are used interchangeably,except where otherwise clearly intended to have different meanings.

The term “agitation”, as used herein, means irritability, emotionaloutburst, impaired thinking, or excess motor and verbal activity thatmay occur due to either dysfunction of specific brain regions such asfrontal lobes or due to dysfunction of neurotransmitter systems such asdopamine and nor-epinephrine. In the present invention, agitation alsoincludes aggression and hyper-arousal in post-traumatic stress disorder.The agitation may be acute or chronic.

The term “the signs of agitation” includes excessive motor activity(examples include: pacing, rocking, gesturing, pointing fingers,restlessness, performing repetitious mannerisms), verbal aggression(e.g. yelling, speaking in an excessively loud voice, using profanity,screaming, shouting, threatening other people), physical aggression(e.g. grabbing, shoving, pushing, clenching hands into fists, resisting,hitting others, kicking objects or people, scratching, biting, throwingobjects, hitting self, slamming doors, tearing things), and destroyingproperty.

The term “without significant sedation” and the like means that thepatient experiences a level of sedation not greater than Level 3 on theRamsay Sedation Scale. Level 3 means sedated but responds to commands.In some embodiments, the dexmedetomidine may be dosed to achieve aRichmond Agitation Sedation Scale (RASS) of −1 (“light sedation”).

The term “dissolvable” means the films herein are readily disintegrated,e.g. at least within about 20 minutes, following administration to theoral mucosa. Disintegration is achieved by saliva and/or other aqueousmaterials on the mucosal surface.

The term “neuropsychiatric conditions” includes, but is not limited to,schizophrenia, bipolar illness (bipolar disorder, bipolar mania),depression, delirium or other related neuropsychiatric conditions.

The term “an effective amount” is interchangeable with “therapeuticallyeffective dose,” or “therapeutically effective amount,” and refers to anamount sufficient to produce the desired effect. An effective amount issufficient to cause an improvement in a condition (e.g. agitation) ofthe subject.

The terms “treating,” and “treatment,” as used herein refer to curativetherapy, prophylactic therapy, and/or preventative therapy and can beused interchangeably.

The term “significantly reduced” refers to a reduction level by at least10% or higher, preferably 20% or higher, more preferably 40% or higher,even more preferably 60% or higher, still more preferably 80% or higher,and 90% or higher, as compared to a control. For example, in the contextof agitation, the a skilled artisan will readily understand that thereduction can be measured in terms of well-known agitation scales, suchas PEC score and CGI-I (described in more detail in the examples). As anexample, when agitation is significantly reduced in a patient, thereduction may be interpreted as as those who achieve at least a 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or greater reduction inPEC total score from baseline (e.g. measured at 2 hours post-dose). Insome embodiments, significantly reduced agitation refers to at least a40% reduction in PEC total score from baseline. Similarly, a significantreduction in agitation may be measured on the CGI-I scale and may referto a patient that has a score of 1 or 2 on the CGI-I scale (e.g.measured at 1, 2, or 4 hours post-dose) or the Agitation-CalmnessEvaluation Scale (ACES) scale and may refer to a patient that has ascore of e.g. 3 or higher.

The term “pharmaceutically acceptable salt” refers to a salt known to benon-toxic and commonly used in the pharmaceutical literature. Typicalinorganic acids used to form such salt include hydrochloric,hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric,and the like. Salts derived from organic acids, such as aliphatic monoand dicarboxylic acids, phenyl substituted alkanoic acids,hydroxyalkanoic and hydroxyl alkandioic acids, aromatic acids, aliphaticand aromatic sulfonic acids may also be used. A preferred salt is thehydrochloride salt.

The term “film” herein includes thin films, sheets and wafers, in anyshape, including rectangular, square, or other desired shape. The filmmay be of any desired thickness and size, such that it can beconveniently placed sub-lingually in the patient. For example, the filmmay be a relatively thin film having a thickness of from about 20micrometers to about 200 micrometers or may be a somewhat thicker filmhaving a thickness of from about 20 micrometers to about 1000micrometers. In certain embodiments, the film may be even thicker, e.g.,having a thickness greater than about 30 millimeters.

As used herein, the phrase “water-soluble polymer” refers to (i) apolymer that is at least partially soluble in water, and desirably fullyor predominantly soluble in water, and/or (ii) a polymer that absorbswater. Polymers that absorb water are referred to herein aswater-swellable polymers.

The term “self-supporting” means the films herein maintain structuralintegrity upon handling without the need for a backing layer. Someflexibility in the film is contemplated and may be desirable.

As used herein, the phrase “disposed within a polymer matrix” means thatdexmedetomidine or a pharmaceutically acceptable salt thereof isincorporated directly into the polymer solution prior to the formationof the solid polymer matrix film composition.

As used herein, the phrase “deposited on the surface of a polymermatrix” means that dexmedetomidine or a pharmaceutically acceptable saltthereof is formulated as liquid composition separate from thepreparation of the solid polymer matrix, and deposited onto the solidpolymer, e.g. as one or more micro-deposits, where it dries. The driedproduct is sometimes referred to herein as the “micro-deposited matrixfilm”. The drug liquid formulation may be in any form, including as asolution, emulsion, suspension, or dispersion.

The term “intranasal administration” means administration by the nasalroute, whereby a drug is insufflated through the nose. Theadministration can be either topical or systemic, meaning the locallydelivered drug can go on to exhibit either purely local or systemiceffects.

The term “parenteral” refers to administration of a drug by injectionunder one or more layer of skin or mucous membrane, and can include, forexample, subcutaneous, intravenous, intraperitoneal or intramuscularinjection.

The term “proportion of treatment responders” is defined as thosesubjects exhibiting about a 40% drop in PEC score at 2 hours.

The term “clinically significant cardiovascular effects” means herein alowering in blood pressure (hypotension) and/or heart rate (bradycardia)to the extent that medical intervention is required to address thecardiovascular side effects, where the term “medical intervention” meansan intervention that more serious than administering fluids, such as anenergy drink.

I. Active Agent

Dexmedetomidine has the IUPAC name (+)4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. As themonohydrochloride salt, it is predominantly used as a medication for thesedation of patients during treatment in an intensive care setting or tosedate patients prior to and/or during surgical and other procedures.Such medication is currently sold under the registered trade name“PRECEDEX”.

Pharmaceutically acceptable salts of dexmedetomidine that may be usedherein include generally any suitable salt that has been or may beapproved by the US FDA or other appropriate foreign or domestic agencyfor administration to a human. Non-limiting examples of suitablepharmaceutically acceptable salts include salts of inorganic acids suchas hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic,phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric,hydrogen sulfuric, and hydroiodic acid. Other examples include saltsderived from non-toxic organic acids, including acetic, propionic,isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric,lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric,tartaric, and methanesulfonic acids, or combinations of these acidsalts. Exemplary salts include dexmedetomidine hydrochloride,dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidinesulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate,dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidinetartrate, dexmedetomidine malate, dexmedetomidine benzoate,dexmedetomidine salicylate, dexmedetomidine ascorbate or the like. Inother embodiments, deuterated forms of dexmedetomidine or apharmaceutically acceptable salt thereof may be included.

II. Dosage

In some embodiments, the dosage of dexmedetomidine or a pharmaceuticallyacceptable salt thereof administered may conveniently be in the range ofbetween about 0.5 μg to about 1200 μg, depending on the route ofadministration etc. Examples of suitable dosages include: about 0.5 μgto about 1200 μg, about 0.5 μg to about 500 μg, about 0.5 μg to about450 μg, about 0.5 μg to about 405 μg, about 0.5 μg to about 360 μg,about 0.5 μg to about 270 μg, about 0.5 μg to about 180 μg, and about0.5 μg to about 120 μg. The dose may be administered one or more times aday including twice, three times, four times, five times or six timesper day.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof may be administered at a dose of about 10 μg to about 300μg, e.g. about 10 μg to 270 μg, about 20 μg to about 240 μg, about 30 μgto about 180 μg, about 40 μg to about 140 μg, about 60 μg to about 120μg, about 70 μg to about 100 μg, about 80 μg to about 100 μg of unitdose total weight of pharmaceutical composition. These doses can beprovided via one or more units to deliver the total dose. Examples ofsuitable doses include (in μg): about 10, about 15, about 20, about 25,about 30, about 35, about 40, about 45, about 50, about 55, about 60,about 65, about 70, about 75, about 80, about 85, about 90, about 95,about 100, about 105, about 110, about 115, about 120, about 125, about130, about 135, about 140, about 145, about 150, about 155, about 160,about 165, about 170, about 175, about 180, about 185, about 190, about195, about 200, about 205, about 210, about 215, about 220, about 225,about 230, about 235, about 240, about 245 and about 250.

In one embodiment, dexmedetomidine or a pharmaceutically acceptable saltthereof may be administered oromucosally (e.g. sublingually or buccally)at a dose of about 10 μg to about 300 μg, e.g. about 10 μg to 270 μg,about 20 μg to about 240 μg, about 30 μg to about 180 μg, about 40 μg toabout 140 μg, about 50 μg to about 120 μg, about 60 μg to about 120 μg,about 70 μg to about 100 μg, about 80 μg to about 100 μg of unit dosetotal weight of sublingual film composition. These doses can be providedvia one or more units to deliver the total dose. Examples of suitabledoses include (in μg): about 10, about 15, about 20, about 25, about 30,about 35, about 40, about 45, about 50, about 55, about 60, about 65,about 70, about 75, about 80, about 85, about 90, about 95, about 100,about 105, about 110, about 115, about 120, about 125, about 130, about135, about 140, about 145, about 150, about 155, about 160, about 165,about 170, about 175, about 180, about 185, about 190, about 195, about200, about 205, about 210, about 215, about 220, about 225, about 230,about 235, about 240, about 245 and about 250.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof may be administered at a dose of about 120 μg to about 405μg, e.g. about 120 μg to about 270 μg, including about 120 μg and about180 μg of unit dose total weight of pharmaceutical composition. Thesedoses can be provided via one or more units to deliver the total dose.Examples of suitable doses include (in μg): about 120, about 125, about130, about 135, about 140, about 145, about 150, about 155, about 160,about 165, about 170, about 175, about 180, about 185, about 190, about195, about 200, about 205, about 210, about 215, about 220, about 225,about 230, about 235, about 240, about 245, about 250, about 255, about260, about 265, about 270, about 275, about 280, about 285, about 290,about 295, about 300, about 305, about 310, about 315, about 320, about325, about 330, about 335, about 340, about 345, about 350, about 355,about 360, about 365, about 370, about 375, about 380, about 385, about390, about 395, about 400 and about 405.

In another embodiment, dexmedetomidine or a pharmaceutically acceptablesalt thereof may be administered oromucosally (e.g. sublingually orbuccally) at a dose of about 120 μg to about 405 μg, e.g. about 120 μgto about 270 μg, including about 120 μg and about 180 μg of unit dosetotal weight of sublingual film composition. These doses can be providedvia one or more units to deliver the total dose. Examples of suitabledoses include (in μg): about 120, about 125, about 130, about 135, about140, about 145, about 150, about 155, about 160, about 165, about 170,about 175, about 180, about 185, about 190, about 195, about 200, about205, about 210, about 215, about 220, about 225, about 230, about 235,about 240, about 245, about 250, about 255, about 260, about 265, about270, about 275, about 280, about 285, about 290, about 295, about 300,about 305, about 310, about 315, about 320, about 325, about 330, about335, about 340, about 345, about 350, about 355, about 360, about 365,about 370, about 375, about 380, about 385, about 390, about 395, about400 and about 405.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof may be administered orally at a dose of about 500 μg toabout 1500 μg, e.g. about 900 μg to about 1200 μg, based on total weightof oral composition. These doses can be provided via one or more unitsto deliver the total dose. Examples of suitable doses include (in μg):about 500, about 510, about 520, about 530, about 540, about 550, about560, about 570, about 580, about 590, about 600, about 610, about 620,about 630, about 640, about 650, about 660, about 670, about 680, about690, about 700, about 710, about 720, about 730, about 740, about 750,about 760, about 770, about 780, about 790, about 800, about 810, about820, about 830, about 840, about 850, about 860, about 870, about 880,about 890, about 900, about 910, about 920, about 930, about 940, about950, about 960, about 970, about 980, about 990, about 1000, about 1010,about 1020, about 1030, about 1040, about 1050, about 1060, about 1070,about 1080, about 1090, about 1100, about 1110, about 1120, about 1130,about 1140, about 1150, about 1160, about 1170, about 1180, about 1190,about 1200, about 1210, about 1220, about 1230, about 1240, about 1250,about 1260, about 1270, about 1280, about 1290, about 1300, about 1310,about 1320, about 1330, about 1340, about 1350, about 1360, about 1370,about 1380, about 1390, about 1400, about 1410, about 1410, about 1420,about 1430, about 1440, about 1450, about 1460, about 1470, about 1480,about 1490 and about 1500.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof may be administered intramuscularly at a dose of about 100μg to about 200 μg, e.g. about 120 μg to about 190 μg, based on totalweight of intramuscular injection. Examples of suitable doses include(in μg): about 100, about 105, about 110, about 115, about 120, about125, about 130, about 135, about 140, about 145, about 150, about 155,about 160, about 165, about 170, about 175, about 180, about 185, about190, about 195 and about 200.

The exemplary dosage of dexmedetomidine or a pharmaceutically acceptablesalt thereof to be administered to a particular patient, will depend onthe type and extent of the condition, the overall health status of theparticular patient, the particular form of dexmedetomidine or apharmaceutically acceptable salt thereof being administered, and theparticular formulation used to treat the patient.

III. Pharmaceutical Compositions

According to the present disclosure, dexmedetomidine or apharmaceutically acceptable salt thereof can be administered to thehuman subject through various routes, including oromucosal (e.g.sublingual, buccal), oral, parenteral and the like. Formulationssuitable for use according to the present disclosure are outlined below.Additional formulations suitable for use according to the presentdisclosure are described in US 2020/0000717, which is herebyincorporated by reference in its entirety for all purposes.

Oromucosal Formulations (Sublingual and/or Buccal Formulations)

Dexmedetomidine or a pharmaceutically acceptable salt thereof can beformulated, according to the present disclosure, into dosage formssuitable for sublingual or buccal administration. Such dosage formsinclude tablets, powders, pills, films, capsules, liquids, gels, syrups,slurries, suspensions, and the like. In one embodiment, dexmedetomidineor a pharmaceutically acceptable salt thereof is formulated as a filmproduct.

Carriers suitable for inclusion in sublingual or buccal formulationsinclude, but are not limited to, sugars, starches, cellulose and itsderivatives, malt, gelatin, talc, calcium sulphate, vegetable oils,synthetic oils, polyols, alginic acid, phosphate buffered solutions,emulsifiers, isotonic saline, pyrogen—free water and combinationsthereof. Carriers which readily dissolve in saliva may be preferred.

Sublingual or buccal formulations may also include otherpharmaceutically acceptable carriers and/or excipients such as binders,lubricants, diluents, coatings, disintegrants, barrier layer components,glidants, colouring agents, solubility enhancers, gelling agents,fillers, proteins, co-factors, emulsifiers, solubilising agents,suspending agents and mixtures thereof. Particular excipients, which maybe used according to this disclosure, are known in the art, for exampleas described in Handbook of Pharmaceutical Excipients, fifth edition,2005 edited by Rowe et al., Mcgraw Hill.

Films

Suitable films for sublingual or buccal administration (i.e. oromucosaladministration) according to the present disclosure comprisedexmedetomidine or a pharmaceutically acceptable salt thereof either (i)disposed within a polymer matrix or (ii) deposited on the surface of apolymer matrix, e.g., on the surface of a “placebo” film.

Polymer Component of Film

The polymer component consists of one or more water-soluble polymerswithin the film matrix and/or as part of the drug-containing deposit(e.g. one or more droplets) on the surface of the polymer. In someembodiments of the disclosure, the polymer component consists of asingle water-soluble polymer. In some embodiments, the polymer componentconsists of two or more water-soluble polymers, including two or more ofthe same water-soluble polymers having different molecular weights.

The polymer component in the film matrix is of a suitable compositionand present in a sufficient amount to ensure rapid disintegration of thefilm matrix in the oral mucosa. For example, the presence of the polymercomponent may allow the film matrix to disintegrate completelyoromucosally in about 15 seconds to about 180 seconds, for example,about 30 seconds to about 180 seconds, including about 120 seconds. Thepolymer component in the film matrix also provides the film withsufficient strength (i.e. the film is self-supporting).

When present in one or more droplets of the dexmedetomidine compositiondeposited onto the surface of the polymer matrix/substrate, the polymercomponent may, for example, consist of the water-soluble polymerhydroxypropyl cellulose, although different water-soluble polymers arealso contemplated as described hereinafter under the definition “firstwater-soluble polymer” and “second water soluble polymer”. For example,the polymer component may consist of one, two or three hydroxypropylcelluloses having different molecular weights. The molecular weights ofthe different hydroxypropyl celluloses may conveniently range from (i)less than about 60,000 daltons (e.g. about 5,000 daltons to about 49,000daltons) (ii) about 90,000 daltons to about 200,000 daltons and (iii)about 200,000 daltons to about 500,000 daltons. The two or morehydroxypropyl celluloses may be mixed in any suitable ratio to achievethe desired droplet viscosity. The viscosity of the dexmedetomidinecomposition solution or suspension can be measured using a Brookfieldviscometer with a small sample adapter at a temperature of 25° C. andmay range from about 5 cps to about 3700 cps. For example, it may rangefrom about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 6cps to about 100 cps or about 6 cps to about 50 cps. In some embodimentsof the present disclosure, the viscosity of the dexmedetomidinecomposition solution or suspension is from about 6 cps to about 20 cpsat 25.0 and a shear rate of about 7 (l/s).

When present in a monolithic (i.e. placebo or drug-containing) film, thepolymer component may, for example, consist of one water soluble polymeror two different water-soluble polymers. When two differentwater-soluble polymers are present, one of the water-soluble polymersmay include the same polymer but present in the polymer component as acombination of different molecular weights. For example, the polymercomponent may consist of one, two or three hydroxypropyl celluloseshaving different molecular weights, although different water-solublepolymers are also contemplated as described hereinafter under thedefinition “first water-soluble polymer” and “second water solublepolymer” such as polyethylene oxide. The molecular weights of thedifferent hydroxypropyl celluloses may conveniently range from (i) lessthan about 60,000 daltons (e.g. about 5000 daltons to about 49000daltons) (ii) about 90000 daltons to about 200000 daltons and (iii)about 200,000 daltons to about 500,000 daltons (e.g. about 300000daltons to about 450000 daltons). The two or more hydroxypropylcelluloses (e.g. low and high molecular weight hydroxypropyl celluloses)may be mixed in any suitable ratio to achieve the desired filmproperties. When present in a monolithic (i.e. placebo ordrug-containing) film or micro-deposited film matrix composition, thepolymer component may conveniently consist of one or more water-solublepolymers having a molecular weight less than about 60,000 daltons (e.g.about 5,000 daltons to about 49,000 daltons), and/or from about 90000daltons to about 200,000 daltons and/or about 200,000 daltons to about500,000 daltons (e.g. about 300000 daltons to about 450000 daltons).When a structurally different water-soluble polymer is also present, itmay conveniently have a higher molecular weight, for example a molecularweight greater than about 500,000 daltons.

In some embodiments, the disclosure provides pharmaceutical filmcompositions, comprising: (i) dexmedetomidine or a pharmaceuticallyacceptable salt thereof; (ii) a polymer component consisting of a firstwater-soluble polymer having a molecular weight less than about 60,000daltons (e.g. about 5,000 daltons to about 49,000 daltons), and one ormore second-water soluble polymers having a molecular weight greaterthan about 60,000 daltons; and, optionally, (iii) one or morepharmaceutically acceptable carriers.

In some embodiments, the disclosure provides pharmaceutical filmcompositions consisting essentially of: (i) dexmedetomidine or apharmaceutically acceptable salt thereof; (ii) a polymer componentconsisting of a first water-soluble polymer having a molecular weightless than about 60,000 daltons (e.g. about 5,000 daltons to about 49,000daltons), and one or more second-water soluble polymers having amolecular weight greater than about 60,000 daltons; and, optionally,(iii) one or more pharmaceutically acceptable carriers.

In some embodiments, the disclosure provides pharmaceutical filmcompositions consisting of: (i) dexmedetomidine or a pharmaceuticallyacceptable salt thereof; (ii) a polymer component consisting of a firstwater-soluble polymer having a molecular weight less than about 60,000daltons (e.g. about 5,000 daltons to about 49,000 daltons), and one ormore second water-soluble polymers having a molecular weight greaterthan about 60,000 daltons; and, optionally, (iii) one or morepharmaceutically acceptable carriers.

Examples of one or more first water-soluble polymers are selected fromthe group consisting of hydroxypropyl cellulose (HPC), hydroxyethylcellulose, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose, methyl cellulose and mixtures thereof, including mixtures ofthe same polymer having different molecular weights.

Examples of one or more second water-soluble polymers are selected fromthe group consisting of hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, carboxy methylcellulose,methylcellulose and mixtures thereof, including mixtures of the samepolymer having different molecular weights. Polyethylene oxide (PEO) mayalso be present herein as a second water-soluble polymer or may bedescribed separately hereinafter in the pharmaceutical film compositionsas an example of a pharmaceutically acceptable carrier, or moreparticularly, as a mucoadhesive agent.

In one embodiment, the weight ratio of said first water-soluble polymerto said second water-soluble polymer(s) (including PEO when present inthe film) in the entire film composition is from about 2:1 to about1:50, for example about 1:1 to about 1:40, including about 1:1, about1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8,about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14,about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20,about 1:21, about 1:22, about 1:23, about 1:24, about 1:25, about 1:26,about 1:27, about 1:28, about 1:29, about 1:30, about 1:31, about 1:32,about 1:33, about 1:34, about 1:35, about 1:36, about 1:37, about 1:38,about 1:39, about 1:40.

In a further embodiment, the weight ratio of said first water-solublepolymer to said second water-soluble polymer(s) (including PEO whenpresent in the film) in the entire film composition is from about 1:10to about 1:30, about 1:15 to about 1:25 or about 1:15 to about 1:20. Insome embodiments, a ratio of about 1:15 to about 1:20 providesbeneficial functional effects.

Examples of other water-soluble polymers which may be included in thefilm with the first water-soluble polymer/second water-soluble polymeror replace such polymer(s) include povidone (polyvinylpyrrolidone),copovidone (copolymers of N-vinyl-2-pyrrolidone and vinyl acetate),polyvinyl alcohol, polyethylene glycol, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl copolymers, polydextrose,pullulan, carboxymethyl cellulose, sodium alginate, chitosan, xanthangum, tragacanth gum, guar gum, acacia gum, arabic gum, starch,carrageenan, gelatin and mixtures thereof. The water-soluble polymercomponent, including water-soluble polymer carriers when present, mayconveniently comprise about 40% to about 99.8%, about 50% to about99.7%, about 60% to about 99.6% of the film composition, based on theweight of the film on a dry weight basis.

In some embodiments, the polymer component for the film compositioncomprises a first water-soluble polymer present in an amount of fromabout 2% to about 15% on a dry weight basis of the polymer component(e.g. at about 3% to about 8% w/w of the total film weight). Thiswater-soluble polymer may conveniently have a molecular weight fromabout 5,000 daltons to about 49,000 daltons. Examples of suitable suchwater-soluble polymers include those selected from the group consistingof hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose, methyl cellulose, and mixturesthereof.

In some embodiments, low molecular weight hydroxypropyl cellulose may bepresent in the film at about 3% to about 8% w/w of the total filmweight.

In some embodiments, the one or more second water-soluble polymers(including water-soluble polymer carriers such as polyethylene oxide)may, for example, be present in an amount of from about 50 to about 98weight percent on dry weight basis of the polymer component. The one ormore second water-soluble polymers each has a molecular weight greaterthan 60,000 daltons; for example, from about 90,000 daltons to about1,500,000 daltons, especially when the polymer is selected from thegroup consisting of polyethylene oxide, hydroxypropyl cellulose,hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof.

In some embodiments, the one or more second water-soluble polymers maytogether be present in the film at about 25% to about 40% w/w of thetotal film weight when the one or more second water-soluble polymerseach has a molecular weight from about 90,000 daltons to about 200,000daltons and/or from about 200,000 daltons to about 500,000 daltons, andthe polymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose,carboxy methylcellulose, methylcellulose, and mixtures thereof.

In some embodiments, a polyethylene oxide may be present in the film atabout 50% to about 60% w/w of the total film weight.

In one embodiment, the polymer component for the film compositionconsists of a low molecular weight, water-soluble polymer (e.g., havinga molecular weight less than about 60,000 daltons) and one or more highmolecular weight polymers (e.g., having a molecular weight greater about60,000, up to about 1,500,000 daltons when a polyethylene oxide isincluded in the polymer mixture or up to about 500,000 daltons when apolyethylene oxide is not included in the polymer mixture). This polymercombination, especially when the polymers are a combination ofhydroxypropyl cellulose and polyethylene oxide, lends certain advantagesto the tensile strength and pharmacokinetics of the film composition.

In some embodiments, the present disclosure provides a film compositioncomprising (e.g. consisting essentially of):

-   -   (i) a therapeutically effective amount of dexmedetomidine or a        pharmaceutically acceptable salt thereof;    -   (ii) a polymer component consisting of one or more water-soluble        polymers: and    -   (iii) one or more pharmaceutically acceptable carriers.

In one embodiment, the present disclosure provides a film compositioncomprising (e.g. consisting essentially of):

-   -   (i) therapeutically effective amount of dexmedetomidine or a        pharmaceutically acceptable salt thereof;    -   (ii) a polymer component consisting of: (a) one or more first        water-soluble polymer (e.g. hydroxypropyl cellulose,        hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy        methylcellulose, methylcellulose, and mixtures thereof) having a        molecular weight from about 5,000 daltons to about 49,000        daltons, for example, in about 2 to about 15 weight percent on        dry weight basis of the total polymer component; and (b) one or        more second water-soluble polymers (e.g. polyethylene oxide,        hydroxypropyl cellulose, hydroxypropyl methylcellulose,        hydroxyethyl cellulose, carboxy methylcellulose,        methylcellulose, and mixtures thereof) having a molecular weight        greater than 60,000 daltons, such as greater than 100000        daltons, for example in about 50 to about 98 weight percent on        dry weight basis of the total polymer component; and    -   (iii) one or more pharmaceutically acceptable carriers.

The molecular weight of hydroxypropyl cellulose, when present in thefilm of the present disclosure, may be varied, and may be present asboth a low molecular weight, water-soluble polymer and as one or morehigh molecular weight, water-soluble polymers. In some embodiments, themolecular weight may be less than about 60,000 daltons (e.g. about 5,000daltons to about 49,000 daltons). In other embodiments the molecularweight may be in the range from about 90,000 daltons to about 200,000daltons. In yet other embodiments, the molecular weight may be in therange from about 200,000 daltons to about 500,000 daltons.

Hydroxypropyl cellulose, when part of the film composition includingpolyethylene oxide, may conveniently be present in the range from about10% to about 90% by weight on a dry weight basis of the polymercomponent, e.g. about 20% to about 80% by weight on dry weight basis ofthe polymer component, e.g. about 20% to about 50% by weight on dryweight basis of the polymer component, e.g. about 25% to about 45% byweight on dry weight basis of the polymer component.

The molecular weight of polyethylene oxide, when present in the film ofthe present disclosure, may also be varied. In some embodiments, awater-soluble, high molecular weight polyethylene oxide may be used, forexample, to increase muco-adhesivity of the film. In certainembodiments, the molecular weight may range from about 100,000 daltonsto about 1,500,000 daltons, including about 100,000, 200,000, 300,000,600,000, 900,000 or 1,000,000 daltons. In some embodiments, it may bedesirable to use a combination of polyethylene oxide having a molecularweight of about 600,000 daltons to about 900,000 daltons withpolyethylene oxide having a molecular weight of about 100,000 daltons toabout 300,000 daltons in the polymer component.

Polyethylene oxide, when part of the film composition, may convenientlybe present range from about 30% to about 90% by weight on a dry weightbasis of the total polymer component, e.g. about 40% to about 85% byweight on a dry weight basis of the polymer component, e.g. about 55% toabout 80% by weight on a dry weight basis of the polymer component.

Such film compositions may contain the drug dispersed within the film,or micro-deposited onto a surface of the film. When micro-deposited onthe surface of a “placebo” film, the drug may conveniently be added aspart of a dexmedetomidine composition as one or more droplets in aliquid carrier, such as a solvent (e.g. an alcohol such as ethanol),optionally together with one or more (e.g. two) water-soluble polymersand/or pharmaceutically acceptable carriers. Suitable water-solublepolymers include (1) a low molecular weight, water-soluble polymer, forexample a low molecular weight, water-soluble polymer having a molecularweight of less than about 60,000 daltons (e.g. a molecular weight ofabout 5,000 daltons to about 49,000 daltons and optionally (2) one ormore (e.g. one or two) high molecular weight, water-soluble polymers,for example a high molecular weight, water-soluble polymer having amolecular weight of greater than about 60,000 daltons (e.g. a molecularweight of from about 60,000 daltons to about 150,000 daltons such ashydroxypropyl cellulose (77,000 MW), hydroxypropyl cellulose (80,000MW), hydroxypropyl cellulose (90,000 MW), or hydroxypropyl cellulose(140,000 MW)) and/or a high molecular weight, water-soluble polymerhaving a molecular weight of greater than about 60,000 daltons (e.g. amolecular weight of from about 200,000 daltons to about 900,000 daltonssuch as hydroxypropyl cellulose (340,000 MW), hydroxypropyl cellulose(370,000 MW), polyethylene oxide (200,000 MW) or polyethylene oxide(600,000 MW)). Each water-soluble polymer may independently be selectedfrom the group consisting of hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,polyethylene oxide and methyl cellulose, e.g. hydroxypropyl celluloseand/or polyethylene oxide.

In some embodiments, the dexmedetomidine composition comprisesdexmedetomidine hydrochloride, a low molecular weight polymer which ishydroxypropyl cellulose and one or two high molecular weight polymerswhich are each hydroxypropyl cellulose in an ethanol solvent.

In one embodiment, the dexmedetomidine composition comprisesdexmedetomidine or a pharmaceutically acceptable salt thereof (e.g.dexmedetomidine hydrochloride), hydroxypropyl cellulose (40,000 MW) andone or both of hydroxypropyl cellulose (140,000 MW) and hydroxypropylcellulose (370,000 MW).

In another embodiment, the dexmedetomidine composition comprisesdexmedetomidine or a pharmaceutically acceptable salt thereof (e.g.dexmedetomidine hydrochloride), and only two hydroxypropyl celluloses,namely hydroxypropyl cellulose (40,000 MW) and hydroxypropyl cellulose(140,000 MW).

In some embodiments, the deposition composition may be in any form,including as a solution, emulsion, suspension or dispersion. Forexample, the dexmedetomidine composition may be added as one or moredroplets in an ethanol-based solution, optionally containing apH-neutralizing agent such as sodium hydroxide. In some embodiments, thefilm substrate surface contains two or more micro-deposited spots ofdexmedetomidine hydrochloride (e.g. two microdeposited spots) in apolymer matrix. The viscosity of deposition solution/suspension mayrange from about 6 cps to about 3700 cps as measured at 25° C. using aBrookfield viscometer with a small sample adapter. As an example, it mayrange from about 5 cps to about 500 cps, about 6 cps to about 200 cps,about 6 cps to about 100 cps or about 6 cps to about 50 cps.

In some embodiments of the present disclosure, the viscosity of thedexmedetomidine composition is from about 6 cps to about 20 cps at 25°C. and a shear rate of about 7 (l/s).

Following drying to remove the solvent, the film comprises a filmsubstrate (e.g. a placebo) with the dexmedetomidine composition aspreviously described but absent the solvent deposited (e.g.micro-deposited) on the surface of the film substrate. The driedcomposition containing dexmedetomidine or a pharmaceutically acceptablesalt thereof (e.g. dexmedetomidine hydrochloride) may cover the whole ofthe film substrate surface or only part of the film substrate surface.

In some embodiments, the dried dexmedetomidine composition appears asone or more discrete drug-containing droplets on the film substratesurface. Alternatively, stenciling may be used to achieve a one or moredefined and discrete regions of drug-containing composition on thesurface of the film substrate.

In some embodiments, the disclosure provides a dry film productcomprising a film substrate with one or more discrete drug-containingdroplets on the film substrate surface, wherein each suchdrug-containing droplet comprises dexmedetomidine or a pharmaceuticallyacceptable salt thereof, and hydroxypropyl cellulose of two molecularweights: hydroxypropyl cellulose (40,000 MW) available as HPC-SSL, andhydroxypropyl cellulose (140,000 MW) marketed under the tradename ofKlucel™ Type JF NF, and wherein the film substrate compriseshydroxypropyl cellulose of three molecular weights: hydroxypropylcellulose (40,000 MW), hydroxypropyl cellulose (140,000 MW), andhydroxypropyl cellulose (370,000 MW) marketed under the tradename ofKlucel™ Type GF NF. In some embodiments, the film substrate alsocomprises polyethylene oxide (600,000 MW) available under the name ofSentry Polyox WSR 205 LEO NF.

In some embodiments, the dry film product comprises a depositioncomposition (also referred to herein as a “dexmedetomidine composition”)comprising: (i) dexmedetomidine hydrochloride, present at about 9% toabout 50% w/w of the deposition composition, e.g. about 15% to about 25%w/w of the deposition composition; (ii) hydroxypropyl cellulose (40,000MW), present at about 5% to about 85% w/w of the deposition composition;(iii) hydroxypropyl cellulose (140,000 MW) present at about 5% to 85%w/w of the deposition composition; and (iv) hydroxypropyl cellulose(370,000 MW) present at about 0% to about 65% w/w of the depositioncomposition. The film also comprises a polymer matrix, wherein thepolymer matrix comprises: (i) hydroxypropyl cellulose (40,000 MW)present at about 3% to about 40% w/w of the polymer matrix; (ii)hydroxypropyl cellulose (140,000 MW) present at about 3% to about 40%w/w of the polymer matrix; (iii) hydroxypropyl cellulose (370,000 MW)present at about 0% to about 30% w/w of the polymer matrix, and (iv)polyethylene oxide (600,000 MW) present at about 55% to about 75% w/w ofthe polymer matrix.

In some embodiments, the dry film product (e.g. a micro-deposited filmproduct) comprises (i) dexmedetomidine hydrochloride, present at about1% to about 50% w/w of the total film weight; (ii) hydroxypropylcellulose (40,000 MW), present at about 2% to about 30% w/w of the totalfilm weight; (iii) hydroxypropyl cellulose (140,000 MW) present at about2% to about 30% w/w of the total film weight; (iv) hydroxypropylcellulose (370,000 MW) present at about 10% to about 50% w/w of thetotal film weight, (v) polyethylene oxide (600,000 MW) present at about40% to about 75% w/w of the total film weight and (vi) optionally otherpharmaceutically acceptable carriers.

In some embodiments, the films disclosed herein combine several types ofhydroxypropyl cellulose (HPC) to provide a film with advantageousproperties. For example, the film composition may contain two or threeof hydroxypropyl cellulose (40,000 MW), hydroxypropyl cellulose (140,000MW) and hydroxypropyl cellulose (370,000 MW) in combination. In certainembodiments, polyethylene oxide (600,000 MW) is included with thesetypes of HPC when part of a monolithic film.

In certain film compositions of the present disclosure, a low molecularweight hydroxypropyl cellulose (e.g. 40,000 MW) is present at about 3%to about 8% (e.g. about 5%) w/w of the total film weight, a highmolecular weight hydroxypropyl cellulose (e.g. 140,000 MW) is present atabout 3% to about 8% (e.g. about 5%) w/w of the total film weight, ahigh molecular weight hydroxypropyl cellulose (e.g. 370,000 MW) ispresent at about 20% to about 40% w/w of the total film weight, and apolyethylene oxide (e.g. 600,000 MW) is present at about 40% to about70%, (e.g. about 50% to about 60%) w/w of the total film weight. In someembodiments, the two high molecular weight, water-soluble polymers aretogether present at about 25% to about 40% w/w of the total film weight.

The selection and ratio of water-soluble polymers can be made to effectcomplete dissolution of the film composition in oral mucosal fluidswithin seconds to minutes, e.g. in about 0.25 minutes to about 15minutes, thus ensuring delivery of a therapeutically effective amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof via theoral mucosa. For example, the film compositions may reside in thesublingual or buccal region of the mouth up to about 15 minutes, up toabout 10 minutes, or up to about 5 minutes, including for a period offrom about 30 seconds to about 15 minutes, about 1 minute to about 10minutes, or about 1 minute to about 5 minutes.

The standard basket or paddle apparatus described in any pharmacopoeiacan be used for in vitro dissolution testing. The selection ofdissolution medium will essentially depend as per the sink conditionsand highest dose of drug. The temperature of dissolution medium shouldbe maintained at 37±0.5° C. and rpm at 50 (see Bala et al., in Int JPharm Investigation, vol. 3(2), pages 67-76).

Films disclosed herein have several functional advantages to promoterapid onset of drug effect. In some embodiments, thin films compositionsof the disclosure have a disintegration time (DT) of about 15 seconds toabout 180 seconds, about 15 seconds to about 160 seconds, about 25seconds to about 150 seconds, about 15 seconds to about 140 seconds,about 15 seconds to about 120 seconds, about 40 seconds to about 120seconds, about 50 seconds to about 120 seconds, for example about 120seconds, when applied sublingually or buccally. A disintegration time inthis time-frame provides optimal onset of drug effects.

In some embodiments, thin film compositions of the invention havemucoadhesion properties that provide practical benefits of localizingthe film to the sublingual location and reducing, or preventing,effective removal prior to dissolution. This quality is particularlyadvantageous in a clinical setting with an agitated subject. Thus, insome embodiments, thin film compositions have a mucoadhesion force (themucoadhesion strength or shear strength) of about 50 g or above, about100 g or above, about 200 g or above, about 300 g or above, about 400 gor above, about 500 g or above, about 600 g or above, about 700 g orabove, about 800 g or above, about 900 g or above, about 1000 g orabove. In some embodiments, the mucoadhesion force is in a range ofabout 300 g to about 4000 g, about 500 g to about 3000 g, or about 1000g to about 2000 g.

Burst strength of the film also contributes to drug delivery. Certainthin film compositions of the invention have a burst strength at orabove 50 g, 100 g, 200 g, 300 g, 400 g, 500 g, 600 g, 700 g, 800 g, 900g, 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 g, 1600 g, 1700 g, 1800g, 1900 g, 2,000 g, 2,500 g, 3,000 g, 3,500 g, 4,000 g, 4,500 g, 5,000g, 5,500 g, 6,000 g, 6,500 g, 7,000 g, 7,500 g, 8,000 g, 8,500 g, 9,000g, 9,500 g, 10,000 g or 15,000 g. For example, the burst strength may bein a range of about 200 g to about 15000 g, about 300 g to about 10,000g, or 400 g to about 5,000 g.

Pharmaceutically Acceptable Carriers

The film compositions may further comprise one or more pharmaceuticallyacceptable carriers that includes, but is not limited to, liquidcarriers, flavours, sweeteners, refreshing agents, antioxidants, pHadjusting agents, permeation enhancers, mucoadhesive agents,plasticizers, bulking agents, surfactants/non-ionic solubilizers,stabilizers, anti-foam agents, colors or the like.

In certain embodiments, the film compositions are substantially free ofacidic buffer or other acidic agents.

Liquid Carriers

According to some embodiments, the pharmaceutically acceptable carrierincludes a liquid carrier. The liquid carrier comprises one or moresolvents useful in the preparation of the polymer matrix (drugcontaining or placebo) and deposition composition on the polymer matrix.In some embodiments, the solvent may be water. In some embodiments, thesolvent may a polar organic solvent including, but are not limited to,ethanol, isopropanol, acetone, butanol, benzyl alcohol and mixturesthereof. In some embodiments, the solvent may be a non-polar organicsolvent, such as methylene chloride, toluene, ethyl acetate and mixturesthereof. Certain solvents are alcohols, especially ethanol, water andmixtures thereof. Desirably, the solvent content in the wet polymermatrix is at least about 30% by weight of the total wet weight of thetotal film composition prior to drying. The subsequent dried filmcomposition will desirably contain less than about 10% by weight ofsolvent, more desirably less than about 8% by weight of solvent, evenmore desirably less than about 6% by weight of solvent and mostdesirably less than about 2% by weight of solvent.

Flavors/Sweeteners/Refreshing Agents

It may be beneficial to add a sweetener, flavoring agent, refreshingagent, taste-masking agent or a combination thereof to the filmcompositions to improve the film composition taste. Flavors may bechosen from natural and synthetic flavoring liquids. An illustrativelist of such agents includes volatile oils, synthetic flavor oils,flavoring aromatics, oils, liquids, oleoresins or extracts derived fromplants, leaves, flowers, fruits, stems and combinations thereof.Non-limiting flavor oils include: spearmint oil, cinnamon oil,peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil ofnutmeg, oil of sage, and oil of bitter almonds. In one embodiment, theflavor is a peppermint oil flavour available as peppermint oil, NF.

The amount may be varied in order to obtain the result desired in thefinal product. Such variations are within the capabilities of thoseskilled in the art without the need for undue experimentation. Ingeneral, amounts of about 0.1% to about 30 wt % may be used in the filmsto supply flavoring. Suitable sweeteners include both natural andartificial sweeteners. Non-limiting examples of suitable sweetenersinclude, e.g.: water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose(dextrose), mannose, galactose, fructose (levulose), sucrose (sugar),high fructose corn syrup, maltose, invert sugar (a mixture of fructoseand glucose derived from sucrose), partially hydrolyzed starch, cornsyrup solids, and dihydrochalcones; water-soluble artificial sweetenerssuch as the soluble saccharin salts, i.e., sodium or calcium saccharinsalts, cyclamate salts and water-soluble sweeteners derived fromnaturally occurring water-soluble sweeteners, such as a chlorinatedderivatives of ordinary sugar (sucrose), known, for example, assucralose. In one embodiment, the sweetener is sucralose.

Flavoring agents, sweeteners and refreshing agents can be added inconventional quantities, generally up to a total amount of about 0.01%to about 10% of the weight of the film on a dry weight basis, e.g. fromabout 0.1% to about 7% of the weight of the film on a dry weight basis,e.g. about 0.1% to about 5% based on the weight of the film on a dryweight basis.

Other taste-masking agents include, for example polymers, oils, orwaxes. In one embodiment, dexmedetomidine or a pharmaceuticallyacceptable salt thereof is coated with a taste-masking agent prior toformulation of the film compositions. In some embodiments, if ataste-masking agent is used to coat the active ingredient, it may bepresent in an amount of from about 5% to about 80% by weight of theparticle or granule containing the active ingredient. In anotherembodiment, the taste-masking agent is present in an amount from about25% to about 35% by weight of the particle or granule containing theactive ingredient.

Antioxidants

Examples of oxygen scavengers or antioxidants that substantially improvelong-term stability of the film composition against oxidativedegradation include sulfite salts, such as sodium sulfite, sodiumbisulfite, sodium metabisulfite and analogous salts of potassium andcalcium. A suitable amount of the sulfite salt (e.g., sodium sulfite) isup to about 5%, e.g. about 0.001% to about 2% based on the weight of thefilm composition on a dry weight basis.

pH-Adjusting Agents/pH-Neutralizing Agents

The absorption of dexmedetomidine or a pharmaceutical acceptable saltthereof through the oral mucosa may increase in an alkalinemicroenvironment. As an example, this may be achieved when the filmcompositions are maintained at a pH of above 6, from about 6 to about 9,or about 6.5 to about 8. In some embodiments, the film may include analkaline substance that increases the pH of the film product.Non-limiting examples of pH-adjusting/pH-neutralizing agents includebicarbonates (e.g., sodium bicarbonate), citrates (e.g., potassiumcitrate), carbonates (e.g., calcium carbonate), lactates (e.g., sodiumlactate), acetates (e.g., calcium acetate), alkaline buffer (e.g.glycine), sodium hydroxide, sodium chloride or the like. An alkalinebuffer, such as glycine, is one example of a pH-neutralizing agent. Asuitable amount of pH-adjusting/pH-neutralizing agent present in thefilm composition includes, for example, up to about 10%, e.g. about 1%to about 5% based on the weight of the film composition on a dry weightbasis

Permeation Enhancer Agents

Certain effective penetration enhancers that promote absorption ofdexmedetomidine or a pharmaceutically acceptable salt thereof across theoral mucosa include alcohols. An alcohol penetration enhancer, such asbutanol, can conveniently be added to the film composition in an amountof up to about 10%, e.g. about 0.1% to about 5%, e.g. about 1% to about3% based on the weight of the film composition on a dry weight basis.

Mucoadhesive Agents

Examples of mucoadhesive agents that can be added to the filmcomposition include, but are not limited to, sodium alginate, sodiumcarboxymethyl cellulose, guar gum, polyethylene oxide, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,karaya gum, methylcellulose, retene, tragacanth and the like. Onemucoadhesive agent is polyethylene oxide, which may conveniently beadded to the film composition in an amount of from about 20% to about90%, e.g. about 40% to about 70% based on the total weight of the filmcomposition on a dry weight basis.

Plasticizers

Plasticizers that can be effectively employed herein includepolyethylene glycol, propylene glycol, tributyl citrate, triethylcitrate and glycerol. Depending on the selected film-forming polymer(s)and other components of the film formulation, a suitable amount ofplasticizer included in the film composition may typically be up toabout 10%, e.g. about 0.1% to about 5%, e.g. about 0.5% to about 5%based on the weight of the film on a dry weight basis. For certainapplications, higher molecular weight polyethylene glycols may beutilized, including polyethylene oxide

Fillers:

Suitable fillers that can be added to a film composition of includestarch, calcium salts, such as calcium carbonate, and sugars, such aslactose, glucose, sucrose, mannose, sorbitol, mannitol, galactitol,sucralose, trehalose and combinations thereof. The amount of filler thatcan conveniently be added to the film formulation is typically up toabout 25%, e.g. about 0.5% to about 20%, e.g. about 1% to about 15%,e.g. about 2% to about 10%, based on the weight of the film compositionon a dry weight basis.

Surfactants/Non-Ionic Solubilizers

The film typically incorporates at least one surfactant/non-ionicsolubilizer including, for example, but are not limited to, a poloxamer,polyoxyl hydrogenated castor oil, glyceryl polyethylene glycoloxystearates, fatty acid glyceryl polyglyceryl esters, polyglycerylesters, and combinations thereof. The amount of surfactant(s) that canbe added to the film composition is typically up to about 5%, e.g. about0.5% to about 3%, e.g. about 1% to about 3% based on the weight of thefilm composition on a dry weight basis.

Anti-Foaming Components

Simethicone is an example of a useful anti-foaming and/or de-foamingagent, although other anti-foaming and/or de-foaming agents may suitablebe used. An anti-foaming and/or de-foaming agent such as simethicone maybe added to the film composition in an amount from about 0.01% to about5.0%, more desirably from about 0.05% to about 2.5%, and most desirablyfrom about 0.1% to about 1.0% based on the weight of the filmcomposition on a dry weight basis.

Colorants

Color additives that may be included in a film composition include food,drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), orexternal drug and cosmetic colors (Ext. D&C). These colors are dyes,their corresponding lakes, and certain natural and derived colorants.Certain examples of color additives are inorganic pigments, such asoxides of iron or titanium, added in concentrations ranging from about0.001% to about 10%, e.g. about 0.01% to about 3%, based on the weightof the film composition on a dry weigh basis. In one embodiment, thecolor used for the dexmedetomidine composition (i.e. the depositcomposition) is different from the color used for the film substrate(e.g. the placebo film). One color of the monolithic film and the filmsubstrate of the micro-deposited film is emerald green, and available asFast Emerald Green Shade (06507). One color of the dexmedetomidinecomposition (i.e. the deposit composition) is a different color from thecolor of the film substrate, e.g. blue (available as FD&C Blue No. 1).In some embodiments of the film embodiments of the present invention,for example, as described in aspects and embodiments hereinabove, is afilm comprising about 180 μg of dexmedetomidine or a pharmaceuticallyacceptable salt thereof containing two blue color microdeposited spotsof dexmedetomidine hydrochloride on the green color film substrate.

In some embodiments of the film embodiments of the present invention,for example, as described in aspects and embodiments hereinabove, is afilm comprising about 120 μg of dexmedetomidine or a pharmaceuticallyacceptable salt thereof.

In one embodiment (A), there is provided a self-supporting, dissolvable,film, comprising:

-   -   (i) about 180 μg of dexmedetomidine or a pharmaceutically        acceptable salt thereof (e.g. the hydrochloride salt);    -   (ii) one or more water-soluble polymers;    -   (iii) a polyethylene oxide and, optionally,    -   (iv) one or more pharmaceutically acceptable carriers.

In another embodiment (B), there is provided a self-supporting,dissolvable, film, comprising:

-   -   (i) about 120 μg of dexmedetomidine or a pharmaceutically        acceptable salt thereof (e.g. the hydrochloride salt);    -   (ii) one or more water-soluble polymers;    -   (iii) a polyethylene oxide and, optionally,    -   (iv) one or more pharmaceutically acceptable carriers.

In a particular embodiment, the just-mentioned one or more water-solublepolymers (ii) of embodiment (A) or (B) above comprises a low molecularweight, water-soluble polymer and two high molecular weight,water-soluble polymers, for example wherein the low molecular weight,water-soluble polymer has a molecular weight from about 5,000 daltons toabout 49,000 daltons (e.g. about 40,000 daltons), and each highmolecular weight, water-soluble polymer has a molecular weight ofgreater than about 60,000 daltons (e.g. where one of the two highmolecular weight, water-soluble polymers has a molecular weight of about140,000 daltons, and the other high molecular weight, water-solublepolymer has a molecular weight of about 370,000 daltons). Eachwater-soluble polymer is, in some embodiments, hydroxypropyl cellulose.The polyethylene oxide, in some embodiments, has a molecular weight ofabout 600,000 daltons.

In certain embodiments, there is provided a pharmaceutical filmcomposition comprising or consisting essentially of therapeuticallyeffective amount of dexmedetomidine or pharmaceutically acceptable saltthereof and one or more excipients selected from polyethylene oxide,hydroxypropyl cellulose, sucralose, peppermint oil, Emerald greencolorant, and FD&C blue colorant.

In another embodiment (C), there is provided a self-supporting,dissolvable, film, comprising:

-   -   (i) about 180 μg of dexmedetomidine or a pharmaceutically        acceptable salt thereof (e.g. the hydrochloride salt);    -   (ii) a low molecular weight, water-soluble polymer having a        molecular weight of about 40,000 daltons;    -   (iii) a high molecular weight, water-soluble polymer having a        molecular weight from about 140,000 daltons;    -   (iv) a high molecular weight, water-soluble polymer having a        molecular weight from about 370,000 daltons; and    -   (v) a water-soluble polyethylene oxide having a molecular weight        of about 600,000 daltons.

In another embodiment (D), there is provided a self-supporting,dissolvable, film, comprising:

-   -   (i) about 120 μg of dexmedetomidine or a pharmaceutically        acceptable salt thereof (e.g. the hydrochloride salt);    -   (ii) a low molecular weight, water-soluble polymer having a        molecular weight of about 40,000 daltons;    -   (iii) a high molecular weight, water-soluble polymer having a        molecular weight from about 140,000 daltons;    -   (iv) a high molecular weight, water-soluble polymer having a        molecular weight from about 370,000 daltons; and    -   (v) a water-soluble polyethylene oxide having a molecular weight        of about 600,000 daltons.

In a particular embodiment of the just-mentioned films of embodiments(C) and (D), the film components excluding dexmedetomidine or apharmaceutically acceptable salt thereof form a single layer filmsubstrate, and dexmedetomidine or a pharmaceutically acceptable saltthereof is present on the surface of the film substrate (e.g. within acomposition comprising dexmedetomidine or a pharmaceutically acceptablesalt thereof, a low molecular weight, water-soluble polymer having amolecular weight of about 40,000 daltons, and a high molecular weight,water-soluble polymer having a molecular weight of about 140,000daltons). Each water-soluble polymer is, in some embodiments,hydroxypropyl cellulose.

In another embodiment (E), there is provided a self-supporting,dissolvable, film, comprising:

-   -   (a) a composition consisting essentially of:        -   (i) about 180 μg of dexmedetomidine hydrochloride;        -   (ii) hydroxypropyl cellulose (40,000 MW); and        -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:        -   (i) hydroxypropyl cellulose (40,000 MW);        -   (ii) hydroxypropyl cellulose (140,000 MW);        -   (iii) hydroxypropyl cellulose (370,000 MW); and        -   (iv) polyethylene oxide (600,000 MW);            wherein the composition of part (a) is present on the            surface of the film substrate (b).

In another embodiment (F), there is provided a self-supporting,dissolvable, film, comprising:

-   -   (a) a composition consisting essentially of:        -   (i) about 120 μg of dexmedetomidine hydrochloride;        -   (ii) hydroxypropyl cellulose (40,000 MW); and        -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:        -   (i) hydroxypropyl cellulose (40,000 MW);        -   (ii) hydroxypropyl cellulose (140,000 MW);        -   (iii) hydroxypropyl cellulose (370,000 MW); and        -   (iv) polyethylene oxide (600,000 MW);            wherein the composition of part (a) is present on the            surface of the film substrate (b).

In a particular embodiment of the just-mentioned films of embodiments(E) and (F), dexmedetomidine hydrochloride is present at about 0.1% toabout 2% w/w of the total film weight, hydroxypropyl cellulose (40,000MW) is present at about 4% to about 8% w/w of the total film weight,hydroxypropyl cellulose (140,000 MW) is present at about 4% to about 8%w/w of the total film weight, hydroxypropyl cellulose (370,000 MW) ispresent at about 25% to about 30% w/w of the total film weight, andpolyethylene oxide (600,000 MW) is present at about 50% to about 60% w/wof the total film weight.

In some embodiments, the pharmaceutical composition of the presentdisclosure provides detectable C_(max) of dexmedetomidine in humanplasma concentration after single dose administration and multiple doseadministrations of the pharmaceutical composition of the presentdisclosure. In some embodiments, the pharmaceutical composition of thepresent disclosure provides a T_(max) of dexmedetomidine in human plasmaconcentration after a single dose administration or multiple doseadministrations of the pharmaceutical composition of the presentdisclosure. In some embodiments, pharmaceutical compositions of thepresent disclosure provides detectable Area Under the Curve (AUC) ofdexmedetomidine and its metabolites in human plasma concentration aftersingle dose administration or multiple dose administrations. In someembodiments, the AUC of dexmedetomidine (or its metabolites) is measuredfrom time 0 (the time of administration) to 12 hours from the time 0 andis expressed as AUC_(0-12 h). In some embodiments, the AUC ofdexmedetomidine (or its metabolites) is measured from time 0 (the timeof administration) to 24 hours from the time 0 and is expressed asAUC_(0-24 h). In some embodiments, the AUC of dexmedetomidine (or itsmetabolites) is measured from time 0 to the last measurableconcentration and is expressed as AUC_(0-last). In some embodiments, theAUC of dexmedetomidine (or its metabolites) is measured from time 0 (thetime of administration) to time extrapolated to infinity and isexpressed as AUC_(0-Inf). In some embodiments, the ranges and values forAUC_(0-last) and AUC_(0-Inf) for dexmedetomidine (or its metabolites)are similar to the ranges and values for AUC_(0-6 h) for dexmedetomidine(or its metabolites). Thus, in some embodiments, the ranges and valuesfor AUC_(0-6 h) disclosed herein can also serve as the ranges and valuesfor AUC_(0-last) and AUC_(0-inf).

In some embodiments, administration of film (E) oromucosally (e.g.sublingually or buccally) to subjects with schizophrenia at about 180 μgof dexmedetomidine hydrochloride resulted in pharmacokinetic parametersfrom about 80% to about 125% of the following values: C_(max) from about100 ng/L to about 800 ng/L, T_(max) from about 1 hours to about 8 hoursand AUC_(last) from about 500 hr*ng/L to about 8900 hr*ng/L. In someembodiments, the C_(max) is about 80 ng/L, about 100 ng/L, about 125ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L,about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450ng/L, and 475 ng/L, about 500 ng/L, about 525 ng/L, about 550 ng/L,about 575 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L,about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about1000 ng/L. In some embodiment, the T_(max) is about 0.8 h, about 0.9 h,about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h,about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6.0 h, about6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h,about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, or about 10 h. Insome embodiments, the AUC_(last) is about 470 hr*ng/L, about 500hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L,about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L,about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L,about 5250 hr*ng/L, about 5500 hr*ng/L, about 5750 hr*ng/L, about 6000hr*ng/L, about 6250 hr*ng/L, about 6500 hr*ng/L, about 6750 hr*ng/L,about 7000 hr*ng/L, about 7250 hr*ng/L, about 7500 hr*ng/L, about 7750hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, about 8500 hr*ng/L,about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L,about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about11250 hr*ng/L, about 11500 hr*ng/L, or about 11875 hr*ng/L. In someembodiments, the film is administered sublingually.

In some embodiments, administration of film (F) oromucosally (e.g.sublingually or buccally) to subjects with schizophrenia at about 120 μgof dexmedetomidine hydrochloride resulted in pharmacokinetic parametersfrom about 80% to about 125% of the following values: C_(max) from about110 ng/L to about 400 ng/L, T_(max) from about 1 hours to about 4 hoursand AUC_(last) from about 500 hr*ng/L to about 4200 hr*ng/L. In someembodiments, the C_(max) is about 80 ng/L, about 100 ng/L, about 125ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L,about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450ng/L, and 475 ng/L, or about 500 ng/L. In some embodiments, the T_(max)is about 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h,about 4.5 h, about 4.75 h, about 5.0 h. In some embodiments, theAUC_(last) is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L,about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L,about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L,about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, orabout 5500 hr*ng/L. In specific embodiment, the film is administeredsublingually.

In some embodiments, the present disclosure provides pharmaceuticalbuccal film compositions comprising or consisting essentially oftherapeutically effective amount of dexmedetomidine or pharmaceuticallyacceptable salt thereof, one or more mucoadhesive polymers and optionalexcipients selected from one or more of plasticizers, penetrationenhancers, coloring agents, sweetening agents, flavoring agents,taste-making agents or salivary stimulants. Mucoadhesive polymers may beselected from hydrophilic polymers and hydrogels. Examples ofhydrophilic polymers include polyvinyl alcohol [PVA], sodium carboxymethylcellulose [NaCMC], hydroxyl propyl methyl cellulose [HPMC],hydroxyl ethyl cellulose and hydroxypropyl cellulose [HPC]. Examples ofhydrogels include anionic polymers like carbopol, polyacrylates,cationic polymers like chitosan and non-ionic polymers like Eudragitanalogues.

Sprays, Drops or Gels

In some embodiments, the present disclosure provides pharmaceuticalspray compositions or drop compositions suitable for sublingual orbuccal administration comprising or consisting essentially of atherapeutically effective amount of dexmedetomidine or pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptableliquids (from about 1% to about 99.995% by weight). Such liquids may besolvents, co-solvents, or non-solvents for dexmedetomidine or apharmaceutically acceptable salt thereof. Examples of pharmaceuticallyacceptable liquids include water, ethanol, dimethyl sulfoxide, propyleneglycol, polyethylene glycol, propylene carbonate, glycerine,N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean,sunflower, peanut, etc.) or the like. The pharmaceutically acceptableliquid is selected either to dissolve dexmedetomidine orpharmaceutically acceptable salt thereof, to produce a stable,homogenous suspension of it, or to form any combination of a suspensionor solution. In addition to these ingredients, spray or dropformulations of dexmedetomidine or pharmaceutically acceptable saltthereof may include one or more excipients such as viscosity modulatingmaterials (e.g. polymers, sugars, sugar alcohols, gums, clays, silicas,and the like, such as polyvinylpyrrolidone (PVP)); preservatives (e.g.,ethanol, benzyl alcohol, propylparaben and methylparaben); flavoringagents (e.g. peppermint oil), sweeteners (e.g., sugars such as sucrose,glucose, dextrose, maltose, fructose, etc.), artificial sweeteners (e.g.saccharin, aspartame, acesulfame, sucralose), or sugar alcohols (e.g.mannitol, xylitol, lactitol, maltitol syrup); buffers and pH-adjustingagent (e.g., sodium hydroxide, citrate, and citric acid); coloringagents; fragrances, chelating agents (e.g., EDTA); UV absorbers andantifoam agents (e.g., low molecular weight alcohols, dimethicone). Inaddition to one or more of the aforementioned ingredients suitable forsublingual or buccal sprays or drops, gel formulations ofdexmedetomidine or pharmaceutically acceptable salt thereof may includeone or more excipients such as viscosity modulating materials (e.g.water soluble or water swellable polymers such as carbopol,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose).

Sprays, drops, and gels may be made by mixing appropriate quantities ofthe foregoing ingredients in accordance with standard good manufacturingpractices. Such excipients may be included in the formulation to improvepatient or subject acceptance or taste, to improve bioavailability, toincrease shelf-life, to reduce manufacturing and packaging costs, tocomply with requirements of governmental regulatory agencies, and forother purposes. The relative amounts of each ingredient should notinterfere with the desirable pharmacological and pharmacokineticproperties of the resulting formulation.

In some embodiments, there is provided an oromucosal spray compositioncomprising or consisting essentially of therapeutically effective amountof dexmedetomidine or pharmaceutically acceptable salt thereof and oneor more pharmaceutically acceptable carrier or excipients.

A patient may, in one embodiment, be treated by administeringsublingually or buccally 1 to 2 actuations from a spray pump. Anadvantage of spray delivery is the ability to easily titrate patients by1 or 2 doses as required by a single actuation.

Pump action sprays are characterized in requiring the application ofexternal pressure for actuation, for example, external manual,mechanical or electrically initiated pressure. This is in contrast topressurized systems, e.g., propellant-driven aerosol sprays, whereactuation is typically achieved by controlled release of pressure e.g.,by controlled opening of a valve.

Various sublingual spray formulations comprising dexmedetomidinehydrochloride at doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg and 180 μgand excipients as described in table 1.

TABLE 1 Sublingual spray formulation embodiments according to thedisclosure Sublingual Spray Formulation Embodiment No. Ingredients 1 2 34 N-methylpyrrolidone ✓ Propylene Glycol ✓ Polyethylene Glycol ✓Glycerine ✓ Ethanol ✓ ✓ ✓ ✓ Sucralose ✓ ✓ ✓ ✓ Peppermint Oil ✓ ✓ ✓ ✓Purified water ✓ ✓ ✓ ✓ Optionally other ✓ ✓ ✓ ✓ pharmaceuticallyacceptable excipients

Various sublingual drop compositions comprising dexmedetomidinehydrochloride at doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg and 180 μgand excipients as described in table 2.

TABLE 2 Sublingual drop formulations embodiments according to thedisclosure Sublingual Drop Formulation Embodiment No. Ingredients 1 2 34 5 6 7 8 9 10 11 12 13 14 Povidone ✓ ✓ ✓ ✓ ✓ N-methylpyrrolidone ✓ ✓ ✓Hydroxypropyl ✓ ✓ ✓ ✓ methylcellulose Carbopol ✓ ✓ ✓ ✓ ✓ Polyethyleneglycol ✓ ✓ Propylene glycol ✓ ✓ ✓ Glycerine ✓ ✓ ✓ Ethanol ✓ ✓ ✓Sucralose ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Peppermint Oil ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓✓ ✓ ✓ ✓ Purified water ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Optionally other ✓ ✓✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ pharmaceutically acceptable excipients

Various sublingual gel compositions comprising dexmedetomidinehydrochloride at doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg and 180 μgand excipients as described in table 3.

TABLE 3 Sublingual gel formulations embodiments according to thedisclosure. Sublingual Gel Formulation Embodiment Nos. Ingredients 1 2 34 5 6 7 8 9 10 11 12 13 14 15 Carbopol ✓ ✓ ✓ ✓ ✓ Hydroxypropyl ✓ ✓ ✓ ✓ ✓methylcellulose Hydroxypropyl cellulose Carboxymethyl ✓ ✓ ✓ ✓ ✓cellulose N-Methylpyrrolidone ✓ ✓ ✓ Propylene glycol ✓ ✓ ✓ Polyethyleneglycol ✓ ✓ ✓ Glycerine ✓ ✓ ✓ Ethanol ✓ ✓ ✓ Sucralose ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓✓ ✓ ✓ ✓ Peppermint oil ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Purified water ✓ ✓ ✓ ✓✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Optionally other ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓pharmaceutically acceptable excipients

Tablets

In some embodiments, the present disclosure provides tablet formulationssuitable for oromucosal administration (e.g. sublingual or buccaladministration) comprising or consisting essentially of therapeuticallyeffective amount of dexmedetomidine or pharmaceutically acceptable saltthereof and one or more pharmaceutically acceptable carrier (from about1% to about 99.995% by weight). Such carriers may be taste maskingagents, diluents, disintegrants, binders, lubricants, glidants,flavouring agents or liquid solvents. Examples of pharmaceuticallyacceptable liquids include water, ethanol, dimethyl sulfoxide, propyleneglycol, polyethylene glycol, propylene carbonate, glycerine,N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean,sunflower, peanut, etc.) or the like. Taste masking agents include, forexample, amberlite, Opadry® AMB TAN, polymethacrylates (especiallyEudragit® L100), sodium starch glycolate (Primojel), carbopol polymers,PEG-5M, sodium acetate, ethylcellulose, betacyclodextrin. Flavouringagents may be, for example, mint powder, menthol, vanillin, aspartame,acesulfame potassium, saccharin. Disintegrants include, for example,sodium starch glycolate, low-substituted hydroxy propyl cellulose,alginic acid, carbon dioxide, carboxymethylcellulose calcium,carboxymethylcellulose sodium, croscarmellose sodium, guar gum,methylcellulose, polacrilin potassium, poloxamer, sodium alginate.Diluents may be, for example, microcrystalline cellulose, dextrates,dextrose, fructose, mannitol, sucralose, sorbitol, starch,pregelatinized starch, sucrose, xylitol, maltose, maltodextrin,maltitol. Binders may be, for example, alginic acid, carbomer, ethylcellulose, gelatine, liquid glucose, guar gum, hydroxyethyl cellulose,methylcellulose, polydextrose, polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropyl cellulose, sodium alginate. At least onelubricant may conveniently be incorporated into the formulation toprevent the powder from adhering to tablet punches during thecompression procedure. Lubricants may be, for example, talc, magnesiumstearate, calcium stearate, glyceryl behenate, hydrogenated castor oil,stearic acid, sodium lauryl sulphate. Glidants are used to promotepowder flow by reducing interparticle friction and cohesion. These areused in combination with lubricants as they have no ability to reducedie wall friction. Glidants, may be, for example, colloidal silicondioxide, calcium silicate, calcium phosphate tribasic.

Various buccal tablet formulations comprising dexmedetomidinehydrochloride at doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg and 180 μgand excipients as described in table 4.

TABLE 4 Buccal tablet formulation embodiments according to thedisclosure. Buccal Tablet Formulation Embodiment No. Ingredients 1 2 3 45 Lactose monohydrate ✓ ✓ ✓ ✓ ✓ Polyethylene oxide ✓ Hydroxypropyl ✓cellulose Hydroxypropyl ✓ methylcellulose Sodium alginate ✓ Xanthan gum✓ Sucralose ✓ ✓ ✓ ✓ ✓ Magnesium stearate ✓ ✓ ✓ ✓ ✓ Talc ✓ ✓ ✓ ✓Optionally other ✓ ✓ ✓ ✓ ✓ pharmaceutically acceptable excipients

Various sublingual tablet compositions comprising dexmedetomidinehydrochloride at doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg and 180 μgand excipients as described in table 5.

TABLE 5 Sublingual tablet formulation embodiments according to thedisclosure. Sublingual Tablet Formulation Embodiment No. Ingredients 1 23 4 5 6 7 8 9 10 Lactose ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Monohydrate Hydroxypropyl ✓✓ methylcellulose Hydroxypropyl ✓ ✓ cellulose Croscarmellose ✓ ✓ ✓ ✓ ✓Sodium Sodium starch ✓ ✓ ✓ ✓ ✓ glycolate Polyethylene ✓ ✓ oxide Xanthangum ✓ ✓ Sodium alginate ✓ ✓ Sucralose ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Magnesium ✓ ✓✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ stearate Optionally other ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓pharmaceutically acceptable excipients

Intranasal Formulations

The compositions of the disclosure may be administered to the nasalcavity in any suitable form. For example, the composition may beadministered to the nasal cavity in the form of a spray emulsion,suspension or solution, as drops or as a powder.

A powder blend according to the present disclosure may be prepared bymixing dexmedetomidine or a pharmaceutically acceptable salt thereofwith inert ingredients that are standard in the art. Such inertingredients include, but are not limited to diluents such as calciumphosphate, lactose, sugars such as dextrose and sucrose, polyols such asmannitol and sorbitol, and microcrystalline cellulose, glidants such ascolloidal silica and lubricants such as magnesium stearate andhydrogenated vegetable oil and surfactants such as polysorbates; andpolyethylene glycol. For preparing a uniform powder blend on a smallscale, a pestle and mortar and/or sieve may be appropriate whereasmechanical mixers are required for larger scale manufacture. There arenumerous types of mixers available and these are widely described in theliterature, for example Chapter 37, Remington: The Science and Practiceof Pharmacy, 20 Edition, Lipincott, Williams and Wilkins, Baltimore,2000.

If the powder composition of the disclosure comprises granules, thesegranules may be produced by techniques well known to those skilled inthe art such as wet granulation, dry granulation (slugging),extrusion/spheronisation, fluid bed granulation and spray congealing.Further details on granulation processes may be found in the literature,for example Chapter 6, Pharmaceutical Principles of Solid Dosage Forms,J. T. Carstensen, Technomic, Lancaster, P A, 1993.

In addition to dexmedetomidine or a pharmaceutically acceptable saltthereof, other ingredients may be incorporated into the granules. Suchother ingredients include, but are not limited to diluents such ascalcium phosphate, lactose, dextrose, mannitol and microcrystallinecellulose, binders such as povidone (polyvinylpyrrolidone),methylcellulose, polyethylene glycol, gelatin and acacia, disintegrantssuch as starch, croscarmellose and crospovidone, glidants such ascolloidal silica, and lubricants such as magnesium stearate andhydrogenated vegetable oil. Methods for preparation of microspheres arewell known to those skilled in the art and include, but are not limitedto, spray drying, interfacial polymerisation, coarcervation/phaseseparation and solvent evaporation. Methods for producing microspheresare described in, for example, Physicochemical Principles of Pharmacy,3rd Edition, pages 357 to 360, A T Florence and D Attwood, Macmillan,London, 1998 and Physical Pharmacy, 4th Edition, pages 516 to 519, AMartin, Wilkins and Wilkins, Baltimore, 1993. The microspheres mayalternatively be produced using the methods described in WO98/30207 andthe documents cited therein.

The powder compositions of the present disclosure may be administered tothe subject in aerosolised form whereby energy from patient inhalation(sniffing) is used to aerosolise the powder into the nasal cavity orwhere the device itself provides the aerosolisation energy, such as viacompressed air. An example of the former device is manufactured byPfeiffer and an example of the latter is the “Monopowder” manufacturedby Valois. The present invention also provides a nasal drug deliverydevice or a dose cartridge for use in a nasal delivery device loadedwith a composition as defined above.

In one embodiment, the compositions of the disclosure also disclose theprocess for preparing the solutions of the disclosure comprises mixingthe components in a suitable solvent such as water, ethanol, propyleneglycol, polyethylene glycol, glycofurol, benzyl benzoate andpolyoxyethylene castor oil derivatives. The compositions may be preparedusing methods known in the art.

The solutions of the present disclosure may also contain otherpharmaceutically acceptable ingredients well known in the art. Suchingredients include, but are not limited to, thickening, adhesive orgelling agents, such as, but are not limited to, celluloses (e.g.hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl celluloseand microcrystalline cellulose), carbomers, polyethylene oxide,poloxamers or polyethylene glycols, antioxidants (for example sodiummetabisulphite), chelating agents (such as edetic acid or one of itssalts), preservatives (such as potassium sorbate, parabens, phenylethylalcohol or benzalkonium chloride), flavours, sweeteners, thickening,adhesive or gelling agents, including, but are not limited to,celluloses such as hydroxypropyl methylcellulose, methylcellulose,hydroxypropyl cellulose, sodium carboxyl cellulose and microcrystallinecellulose, poloxamers, polyethylene glycols, carbomers or polyethyleneoxide.

The solutions of the disclosure may contain a preservative and/or aresterile. If preservatives are omitted from the compositions,microorganisms may be removed using any suitable method known in theart, for example by making the compositions aseptically or by terminallysterilising them. In some embodiments, the compositions of the inventionare non-pyrogenic.

In one embodiment, intranasal compositions of the present disclosurecomprise aqueous suspension, solution, or emulsion containing materialsin addition to the active ingredient, such as suitable dispersant and/orwetting agent, for example propylene glycol or polyethylene glycol,emulsifier, suspending agent, surfactant, solubilizer, vehicle etc.

The pharmaceutical composition may also be formulated as liposomes,microcapsules or centrosomes, with one or more suitable pharmaceuticallyacceptable carrier.

In addition to dexmedetomidine or a pharmaceutically acceptable saltthereof, microspheres used in the present disclosure may includeingredients that are known in the art to be suitable to be included inmicrospheres such as, but are not limited to, starches, dextrans,gelatin, albumin, collagen, hyaluronic acid, chitosan, lactose, sucrose,dextrose, mannitol, methacrylate copolymers such as the Eudragit®polymers (Degussa, Germany), celluloses such as methylcellulose, andpolyesters such as poly(lactide-co-glycolide).

Any device that is suitable for intranasal administration can be used.In some embodiments, the device is a metered dose device. The metereddose device can deliver a specific dosage amount of the composition. Themetered dose device can be a unit-dose, bi-dose, or a multi-dose device.The pharmaceutically effective amount that can be administered using ametered dose device can be a unit dose device. The metered dose can, insome embodiments, be a device that can deliver a pharmaceuticalcomposition intranasally. Examples of metered dose devices include, butare not limited to, devices that are pump devices, mechanical devices,pressurized devices, and/or electromechanical devices. Examples of ametered dose device include, but are not limited to, a spray pump, apre-compression nasal spray pump, a metered valve device, an actuatedspray device, a side actuated spray device, a syringe nasal spray device(e.g. a syringe that has an atomizer to deliver a spray to the nasalcavity), a mucosal atomization device, an electromechanical pump device(with and without a counter), and the like. Examples of metered dosedevices also include, but are not limited to, devices manufactured byAptar Pharma (Congers, NY) and are commercially available. Examples ofmetered dose devices also include, but are not limited to, UDS (AptarPharma), BDS (Aptar Pharma), eDevices (Aptar Pharma), Equadel (AptarPharma), Latitude (Aptar Pharma), DF30 (Aptar Pharma), VP7 (AptarPharma), Classic Nasal Device (Aptar Pharma), MAD Nasal Drug Device(Wolf Tory Medical, Inc.), BD Accuspray SCF™ (Becton Dickinson), and thelike. Another example includes, but is not limited to, an Aptar UnitdoseIntranasal System.

Parenteral Formulations:

Liquid pharmaceutical compositions for parenteral administration may beformulated for administration by injection or continuous infusion.Routes of administration by injection or infusion can include, but arenot limited to, intravenous, intraperitoneal, intramuscular,intrathecal, and subcutaneous. In some embodiments, parenteralformulations can include prefilled syringes, vials, powder for infusionfor reconstitution, concentrate for infusion to be diluted beforedelivery (ready to dilute) or solutions (ready to use).

Injectable pharmaceutical compositions can be aqueous isotonic solutionsor suspensions, and suppositories can be prepared from fatty emulsionsor suspensions.

The pharmaceutical compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances.

In certain embodiments, the pharmaceutical compositions of the presentdisclosure include biodegradable subcutaneous implant, osmoticallycontrolled device, subcutaneous implant, subcutaneous sustained releaseinjection, lipid nanoparticles, liposomes, and the like. Liquidpreparations can include, but are not limited to, solutions, suspensionsand emulsions. Such preparations are exemplified by water orwater/propylene glycol solutions for parenteral injection. Liquidpreparations may also include solutions for intranasal administration.

For intramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions of the active ingredient(s) are usually employed, andthe pH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of the solute(s) should becontrolled to render the preparation isotonic.

The liquid vehicle used for the preparation of the intramuscularinjection may be, for example, water, a saline solution, another aqueousliquid (aqueous solvent) or non-aqueous liquid (non-aqueous solvent).Non-aqueous solvents may include organic solvents such as ethanol,isopropyl alcohol, diethylene glycol monoethyl ether or other alkylderivative, polyol (e.g., glycerol, propylene glycol, and liquidpolyethylene glycol, and the like) or oily vehicles such as castor oil,arachis oil, sesame oil, or other solvents such ascarboxymethylcellulose, polysorbate and mixtures thereof. These aqueousand non-aqueous solvents can also act as a co-solvent to increase thesolubility of drugs or to reduce the viscosity of oily vehicles.

The formulation may contain an excipient. Pharmaceutically acceptableexcipients which may be included in the formulation are buffers such ascitrate buffer, phosphate buffer, acetate buffer, and bicarbonatebuffer; amino acids; urea; alcohols; ascorbic acid; phospholipids;proteins, such as serum albumin, collagen, and gelatin; salts such asEDTA or EGTA, and sodium chloride; liposomes; polyvinylpyrrolidones;sugars, such as dextran, mannitol, sorbitol, and glycerol; propyleneglycol and polyethylene glycol (e.g., PEG-4000, PEG-6000); glycerol;glycine; lipids; preservatives; suspending agents; stabilizers; anddyes. As used herein, the term “stabilizer” refers to a compoundoptionally used in the pharmaceutical compositions of the presentinvention in order to avoid the need for sulphite salts and increasestorage life. Non-limiting examples of stabilizers include antioxidants.Buffer systems for use with the formulations include citrate; acetate;bicarbonate; and phosphate buffers.

The formulation also may contain a non-ionic detergent. Examples ofnon-ionic detergents include but are not limited to Polysorbate 20,Polysorbate 80, Triton X-100, Triton X-114, Nonidet P-40, Octylα-glucoside, Octyl β-glucoside, Brij 35, Pluronic, and Tween 20.

The parenteral formulations of the present disclosure can be sterilized.Non-limiting examples of sterilization techniques include filtrationthrough a bacterial-retaining filter, terminal sterilization,incorporation of sterilizing agents, irradiation, and heating.

Administration of the above-described parenteral formulations may be byperiodic injections of a bolus of the preparation, or may beadministered by intravenous or intraperitoneal administration from areservoir which is external (e.g., an intravenous bag) or internal(e.g., a bioerodable implant, a bioartificial or organ). See, e.g., U.S.Pat. Nos. 4,407,957 and 5,798,113, each incorporated herein by referencein their entireties. Intrapulmonary delivery methods and apparatus aredescribed, for example, in U.S. Pat. Nos. 5,654,007, 5,780,014, and5,814,607, each incorporated herein by reference in their entireties.Other useful parenteral delivery systems include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, pumpdelivery, encapsulated cell delivery, liposomal delivery,needle-delivered injection, needle-less injection, nebulizer,aerosolizer, electroporation, and transdermal patch. Needle-lessinjector devices are described in U.S. Pat. Nos. 5,879,327; 5,520,639;5,846,233 and 5,704,911, the specifications of which are hereinincorporated herein by reference in their entireties. Any of theformulations described herein can be administered in these methods.Further injectable formulations of dexmedetomidine are disclosed in U.S.Pat. Nos. 8,242,158, 9,649,296, JP. Patent No. 5,921, 928, JP. Pat.Appl. No. 2016154598, CN Pat. Appl. No. 103284945, CN Pat. Appl. No.104161760, CN Pat. Appl. No. 105168122, CN Pat. Appl. No. 105534891, CNPat. Appl. No. 106038538, U.S. Pat. Appl. No. 20170128421, CN Pat. Appl.No. 107028880, CN Pat. Appl. No. 107412152, CN Pat. Appl. No. 108498469,EP Patent. No. 2252290, JP. Pat. Appl. No. 2019048091 and U.S. Pat.Appl. No. 20190183729.

In certain non-limiting embodiments, the dexmedetomidine intramuscularcomposition of the present disclosure comprises dexmedetomidine, or apharmaceutically acceptable salt thereof, at a concentration of betweenabout 0.05 μg/mL and about 15 μg/mL, sodium chloride at a concentrationof between about 0.01 and about 2.0 weight percent and pH in the rangeof about 1 to about 10.

Oral Formulations:

The present disclosure includes oral formulations that can be used fordelivering dexmedetomidine. Examples of oral formulations includestablets, orally disintegrating tablets, mouth dissolving tablets,wafers, solution, suspension, emulsions, and capsules.

The disclosure encompasses oral disintegrating tablets comprisingdexmedetomidine or a pharmaceutically acceptable salt thereof and atleast one orally disintegrating carrier, wherein the oral disintegratingtablet disintegrates in about 0.5 to about 120 seconds and/or atherapeutically effective amount of the dexmedetomidine is absorbed intothe bloodstream within about 1 to about 5 minutes. In some embodiments,a therapeutically effective amount of the dexmedetomidine is absorbedinto the bloodstream within about 3 minutes.

In some embodiments, the at least one orally disintegrating carrier isselected from the group consisting of water-soluble sugars or sugaralcohol, crospovidone, (low-substituted) hydroxypropyl cellulose,croscarmellose sodium, microcrystalline cellulose, lactose,pregelatinized starch, sodium starch glycolate, sodium lauryl sulphate,crystalline cellulose and the combination thereof. The water-solublesugars or sugar alcohol is selected from the group consisting ofsucrose, sorbitol, mannitol, xylitol, erythritol, isomalt and fructose.In some embodiments, the orally disintegrating carriers togetherconstitute at least 50 wt. %, for example at least 80 wt. % or at least85 wt. % of the orally disintegrating carriers. The aforementionedcarriers are in the form of particles typically have a volume weightedmean particle size of 50-300 micrometers, for example of 70-200micrometers. F-Melt® (Fuji Chemical Industry Co.) is an example of acommercially available particulate material that contains adisintegrating agent dispersed in a matrix containing C4-C6 sugaralcohol (mannitol and xylitol). Ludiflash® (BASF) is another example ofa commercially available particulate material that contains adisintegrating agent dispersed in a matrix of C4-C6 sugar alcohol(mannitol).

The orally disintegrating tablet as used herein may be prepared bymixing the dexmedetomidine with water-soluble diluents and compressed ina tablet. A suspension comprising dexmedetomidine may be prepared withappropriate excipients and the dexmedetomidine suspension may bedispensed into blister packs and freeze-dried. An exemplary freeze-driedpreparation platform that could be used for the dexmedetomidine ODT isthe ZYDIS® (Catalent, Somerset, NJ, USA) formulation. In particular, theexcipients, including water, are blended and the dexmedetomidine isseparately milled to size and mixed with the excipients. The suspensionthen undergoes lyophilization by flash freezing and freeze drying. Othermethods of preparing ODTs may be used without limitation, and detaileddescription of general methods thereof have been disclosed, for example,in U.S. Pat. Nos. 5,631,023; 5,837,287; 6,149,938; 6,212,791; 6,284,270;6,316,029; 6,465,010; 6,471,992; 6,471,992; 6,509,040; 6,814,978;6,908,626; 6,908,626; 6,982,251; 7,282,217; 7,425,341; 7,939,105;7,993,674; 8,048,449; 8,127,516; 8,158,152; 8,221,480; 8,256,233; and8,313,768, each of which is incorporated herein by reference in itsentirety.

A liquid pharmaceutical suspension of the present disclosure for oraladministration contains at least one particulate drug as activeingredient wherein active ingredient is dexmedetomidine or apharmaceutically acceptable salt thereof. The particulatedexmedetomidine may be partially dissolved in the liquid phase, butpreferably more than about 50 percent should be particulates. Thesuspension of the present disclosure contains at least one suspendingpolymer exhibiting plastic flow that imparts a yield value of about 0.2to about 15 Pa, preferably from about 0.5 to about 10 Pa Polymersexhibiting Bingham plastic and shear-thinning plastic flow arepreferred. Polymers exhibiting thixotropic plastic flow can be used onlyif the lag time to recover 50% of the yield value is fast, less thanabout an hour, preferably less than about five minutes, most preferablyless than about a minute. The polymer exhibiting plastic flow may beselected from but are not limited to xanthan gum, carbomer,microcrystalline cellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, and combinations thereof. The final yield valueof the suspension must be less than about 15 Pa, preferably less thanabout 10 Pa to ensure that the product is pourable without shaking.

In addition to a yield value, the rheology of the final suspensionshould have an apparent viscosity of at least about 50 cps, preferablyat least about 100 cps, most preferably at least about 200 cps, at ashear rate of 100 sec-1 to retard particle motion when the shear rateexceeds the yield value such as when shaking or pouring. For thixotropicplastic fluid, the high viscosity retards particle motion while theyield value is recovering after application of shear. When thesuspending polymer(s) added to impart the yield value is not adequate toachieve the desired apparent viscosity of at least about 50 cps at ashear rate of 100 sec-1, viscosity-building agents with no yield valuecan be added. These viscosity-building agents may be selected from butare not limited to hydroxypropyl cellulose, hydroxypropylmethylcellulose, povidone, guar gum, locust bean gum, and combinationsthereof.

The liquid suspension of the present disclosure may contain additionalingredients used in the drug industry, herein referred to as additives.Additives include well-known components, but are not limited tosweetening agents, flavors, colorants, antioxidants, chelating agents,surfactants, wetting agents, antifoaming agents, pH modifiers,acidifiers, preservatives, cosolvents, and mixtures thereof.

The present disclosure concerns also a homogeneous and stablepharmaceutical solution of dexmedetomidine suitable for oraladministration to a mammal.

The oral liquid pharmaceutical solution of this disclosure comprisesdexmedetomidine or a pharmaceutically acceptable salt thereof and one ormore pharmaceutically acceptable excipient which is selected from thegroup comprising co-solvents, solvents, antioxidants, microbialpreservatives, buffering agents, aromatic agents, sweeteners anddiluents.

Co-solvents and solvents may include but are not limited to glycerine,alcohols, propylene glycol, polyethylene glycol, benzyl alcohol, water,ethanol, isopropyl alcohol or their mixtures thereof.

Suitable antioxidants may include but are not limited to butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid,beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid sodiumascorbate, sodium bisulfite, sodium metabisulfite, monothioglycero,cysteine, thioglycolate sodium, acetone sodium bisulfite, ascorbate(sodium/acid), bisulfite sodium, cystein/cysteinate HCl, dithionitesodium (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acidethanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium,metabisulfite potassium, metabisulfite sodium, monothioglycerol(thioglycerol), propyl gallate, sulfite sodium, tocopherol alpha,thioglycolate sodium, EDTA in calcium and sodium compounds or themixtures thereof.

Buffering agents may include but are not limited to ascorbic acid,acetic acid, tartaric acid, citric acid monohydrate, trisodium citratedehydrate, sodium citrate, potassium citrate, sodium phosphate,tricalcium phosphate, calcium carbonate, sodium bicarbonate, calciumphosphate, carbonated calcium phosphate, magnesium hydroxide,hydrochloric acid, sodium hydroxide or their mixtures thereof.

Diluents may include but are not limited to maltitol solution, glucosesyrup, glycerin, sorbitol and mannitol solutions, sucrose, sorbitol,xylitol, dextrose, fructose, sugar potassium, aspartame, saccharine,saccharine sodium, spray dried or anhydrase lactose, mannitol, starch ortheir mixtures thereof.

Sweeteners may include but are not limited to sucralose, aspartame,acesulfame-K, thaumatin, mogroside, saccharin and salts thereof, sodiumcyclamate, glucose, sucrose, lactose, fructose, mannitol, sorbitol,lactitol, xylitol, erythritol, glycyrrhizin, monosodium glycyrrhizinate,monoamonium glycyrrhizinate, isomalt, glycerine, dextrose or theirmixtures thereof.

Aromatic agents may include but are not limited to fruit aromas such asorange, banana, strawberry, cherry, wild cherry, lemon and the like, andother aromas such as cardamom, anis, mint, menthol, vanillin or theirmixtures thereof.

Microbial preservatives may include but are not limited to sodiumbenzoate, benzoic acid, boric acid, sorbic acid and their salts thereof,benzyl alcohol, benzalkonium chloride, parahydroxybenzoic acids andtheir alkyl esters, methyl and propyl parabens or their mixturesthereof.

In one embodiment, the present disclosure relates to an oral solidpharmaceutical composition, e.g. in form of a tablet, comprisingpharmacologically effective amounts of dexmedetomidine or apharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable excipient. The compositions of thedisclosure comprise additives conventional in the dosage form inquestion. Tabletting aids, commonly used in tablet formulation can beused and reference is made to the extensive literature on the subject,see in particular Fiedler's “Lexikon der Hilfsstoffe”, 4th Edition, ECVAulendorf, 1996, which is incorporated herein by reference. Theseinclude but are not limited to disintegrants, binders, lubricants,glidants, stabilising agents, fillers or diluents, surfactants and thelike.

As disintegrants suitable for compositions of this disclosure, one canparticularly mention crosslinked PVP, crospovidone, guar gum, alginicacid, sodium alginate, crosslinked CMC and Ac-Di-Sol®. In someembodiments, the disintegrant is crospovidone.

As binders suitable for compositions of this disclosure, one canparticularly mention starches, e.g. potato starch, wheat starch, cornstarch, celluloses such as microcrystalline cellulose, e.g. productsknown under the registered trademarks Avicel®, Filtrak®, Heweten® orPharmacel®, hydroxypropyl cellulose, hydroxyethyl cellulose, andhydroxypropylmethyl cellulose, e.g. hydroxypropyl cellulose having ahydroxypropyl content of 5 to 16% by weight and a molecular weight offrom 80 000 to 1 150 000, more particularly 140 000 to 850 000.

As glidants suitable for compositions of this disclosure, one canmention in particular colloidal silica, e.g. Aerosil®, magnesiumtrisilicate, powdered cellulose, starch, talc, and tribasic calciumphosphate.

As fillers or diluents suitable for compositions of this invention, onecan mention confectioner's sugar, compressible sugar, dextrates,dextrin, dextrose, lactose, mannitol, sorbitol, sucrose,microcrystalline cellulose, in particular having a density of about 0.45g/cm3, e.g. Avicel®, or powdered cellulose, and talc.

A preferred filler may be Avicel®.

As lubricants suitable for compositions of this disclosure, one canmention in particular magnesium-, aluminium-, or calcium-stearate,polyethylene glycol (PEG) having a molecular weight of 4,000 to 8,000,and talc.

One or more of these additives may be selected and used by the skilledartisan having regard to the particular desired properties of the solidoral dosage form by routine experimentation and without any undueburden. The amount of each type of additive employed, e.g. glidant,binder, disintegrant, filler or diluent and lubricant may vary withinranges conventional in the art. For example, the amount of glidant mayvary within a range of from 0.1 to 10% by weight, in particular 0.1 to5% by weight, e.g. 0.1 to 0.5% by weight; the amount of binder may varywithin a range of from about 10 to 65.3% by weight, e.g. 10 to 45%, e.g.20 to 30% by weight; the amount of disintegrant may vary within a rangeof 5 to 60% by weight, e.g. 13 to 50%, e.g. 15 to 40%, e.g. 20 to 30%,e.g. 25%; the amount of filler or diluent may vary within a range offrom 15 to 65% by weight e.g. 20 to 50%, e.g. 25 to 40%, e.g. 30%,whereas the amount of lubricant may vary within a range of from 0.1 to5.0% by weight.

IV. Methods and Administration

In some embodiments (A), the present disclosure provides a method oftreating a condition (e.g. agitation) in a human subject, comprisingadministering dexmedetomidine or a pharmaceutically acceptable saltthereof as a single dose of at least about 120 μg to said subject. Insome embodiments, the treatment is effective without causing significantsedation. In some embodiments, the condition is agitation or signs ofagitation. In some embodiments, the agitation or signs of agitation areassociated with schizophrenia. In some embodiments, the agitation orsigns of agitation are associated with a bipolar illness such as bipolarI disorder. In some embodiments, the treatment is effective withoutcausing clinically significant cardiovascular effects.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered at a dose of about 120 μg to about 405 μg,such as about 120 μg to about 270 μg, or at a dose of about 180 μg toabout 405 μg, such as about 180 μg to about 270 μg, includingadministering doses of about 120 μg or about 180 μg.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered at a dose of about 120 μg to about 405 μg,such as about 120 μg to about 270 μg, or at a dose of about 180 μg toabout 405 μg, such as about 180 μg to about 270 μg, includingadministering doses of about 120 μg or about 180 μg, to treat agitationor signs of agitation in a human subject.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered at a dose of about 120 μg to about 405 μg,such as about 120 μg to about 270 μg, or at a dose of about 180 μg toabout 405 μg, such as about 180 μg to about 270 μg, includingadministering doses of about 120 μg or about 180 μg, to treat agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered at a dose of about 120 μg to about 405 μg,such as about 120 μg to about 270 μg, or at a dose of about 180 μg toabout 405 μg, such as about 180 μg to about 270 μg, includingadministering doses of about 120 μg or about 180 μg, to treat agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation or causingclinically significant cardiovascular effects.

In some embodiments (B), the present disclosure provides a method oftreating agitation or signs of agitation in a human subject withschizophrenia or bipolar disorder, without also inducing significantsedation, comprising administering dexmedetomidine or a pharmaceuticallyacceptable salt thereof (e.g. the hydrochloride salt) as a single doseof about 120 μg or about 180 μg. In some embodiments, the treatment iseffective without causing clinically significant cardiovascular effects.

In some embodiments, the present disclosure provides a method oftreating acute agitation associated with schizophrenia and bipolardisorder (e.g. bipolar I disorder) in a human subject, comprisingoromucosally administering a film composition comprising dexmedetomidineor a pharmaceutically acceptable salt thereof (e.g. hydrochloride salt)as a single dose of 120 μg or 180 μg. In some embodiments, an additionaldose (e.g. 90 μg or 60 μg) may be taken after a suitable period of time(e.g. 2-hours) in the event of persistent or recurrent agitation (e.g.by cutting a 180 or 120 μg film in half).

In some embodiments, the present disclosure provides a method oftreating acute agitation associated with schizophrenia and bipolardisorder (e.g. bipolar I disorder) in a human subject, comprisingoromucosally administering a film composition comprising dexmedetomidineor a pharmaceutically acceptable salt thereof (e.g. hydrochloride salt),wherein the subject is co-treated with an anti-psychotic agent. Suitableanti-psychotic agents contemplated within the scope of the presentdisclosure include but are not limited to aripiprazole, benperidol,flupentixol, amisulpride, chlorpromazine, asenapine, risperidone,ziprasidone, lurasidone, clozapine, cariprazine, olanzapine andquetiapine. In some embodiments, the anti-psychotic agent isaripiprazole.

In a particular embodiment (C), the present disclosure provides methodsof treating agitation or signs of agitation in a human subject withdementia, without also inducing significant sedation, comprisingadministering from about 30 μg to about 180 μg of dexmedetomidine or apharmaceutically acceptable salt thereof. In some embodiments, 30 μg, 60μg or 90 μg of dexmedetomidine or a pharmaceutically acceptable saltthereof are administered as a single dose in a day. In some embodiments,an additional dose (e.g. 30 μg) may be taken after a suitable period oftime (e.g. 2, 4, 6, 8, or 12 hours) in the event of persistent orrecurrent agitation. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof is oromucosally administered asa unit dose containing about 30 μg to about 90 μg between 1 and 6 timesin a day. For example, dexmedetomidine or a pharmaceutically acceptablesalt thereof is oromucosally administered 1, 2, 3, 4, 5, or 6 timesevery 2 hours, every 4 hours, every 6 hours, every 8 hours, every 10hours, or every 12 hours. In some embodiments, each unit dose containingabout 30 to 60 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof may be taken one to six times in a day at an interval of 2hours with the provision of maximum of three doses within 12 hours offirst dose. In some embodiments, each unit dose containing about 90 μgof dexmedetomidine or a pharmaceutically acceptable salt thereof may betaken one to four times in a day at an interval of 2 hours with theprovision of maximum of two doses within 12 hours of first dose. In someembodiments, dexmedetomidine or a pharmaceutically acceptable saltthereof is administered oromucosally (e.g. sublingually or buccally) asa film. In some embodiments, the dosing may be achieved by cutting afilm in half to deliver a half-dose (e.g. a 60 μg dose may beadministered with a half of a second 60 μg dose (30 μg) to make a 90 μgdose.).

In a particular embodiment (D), the present disclosure also providesmethods of managing or treating agitation in delirium in subjects,without also inducing significant sedation, comprising administeringabout 20 μg to about 240 μg of dexmedetomidine or a pharmaceuticallyacceptable salt thereof. In some embodiments, the subject ishospitalized. In some embodiments, the subject is hospitalized in theintensive care unit. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof (e.g. the hydrochloride salt)is oromucosally administered at a unit dose containing about 20 μg orabout 60 μg as a single dose. In some embodiments, each unit dose may beadministered one to four times at an appropriate dosing interval (e.g.every 0.5 hour, 1 hour, 2 hours, or 3 hours) within 6 hours of firstdose to produce a desired effect; for example, 20 μg unit isadministered four times at a dosing interval of 0.5 hours within 6 hoursof first dose to produce the effect of a 80 μg dose or 60 μg unit isadministered four times at a dosing interval of 0.5 hours within 6 hoursof first dose to produce the effect of 240 μg dose. In some embodiments,the treatment is effective without causing clinically significantcardiovascular effects. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof is administered oromucosally(e.g. sublingually or buccally) as a film described herein.

In a particular embodiment (E), the present disclosure provides a methodof reducing a period of opioid withdrawal in a human subject in needthereof, comprising administering to said subject dexmedetomidine or apharmaceutically acceptable salt thereof twice daily, wherein the periodof withdrawal is up to 14 days. In some embodiments, the period ofwithdrawal may be 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7days, 6 days, 5 days, 4 days, or 3 days. In some embodiments, the humansubject is an adult (i.e. at least 18 years old) and suffering withopioid use disorder who is physically dependent on opioids. In someembodiments, dexmedetomidine or a pharmaceutically acceptable salt isadministered sublingually, buccally, orally, intranasally orparenterally. In some embodiments, dexmedetomidine or a pharmaceuticallyacceptable salt (e.g. hydrochloride) is administered sublingually as afilm. In some embodiments, dexmedetomidine or a pharmaceuticallyacceptable salt thereof is oromucosally administered at a dose range ofabout 30 μg to about 200 μg as a single dose. In some embodiments,dexmedetomidine is administered as a dose of about 30 μg, about 60 μg,or about 90 μg, about 120 μg or about 180 μg, twice daily approximately12 hours apart for a period of at least 3 days (e.g. 3 days, 4 days, 5days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days or 13days). In further embodiments, each unit may be administered at anappropriate dosing interval (e.g. about 12 hours between doses) or canbe administered concurrently, for example two units of 30 μg can beadministered concurrently to produce the effect of a 60 μg dose or threeunits of 60 μg can be administered concurrently to produce the effect ofa 180 μg dose. In an embodiment, the withdrawal symptoms following thetreatment are assessed using the Clinical Opiate Withdrawal Scale and/orthe Short Opiate Withdrawal Scale of Gossop (e.g. over a 10-day period).In some embodiments, the opioid may be selected from the groupconsisting of, but are not limited to fentanyl, morphine, codeine,heroin, oxycodone, hydrocodone, alfentanil carfentanil, tramadol,hydromorphone, buprenorphine, naloxone, naltrexone, remifentanilbutorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene)thebaine, sufentanil or pentazocine. In some embodiments, the opioid hadbeen administered for the amount of time longer than neonate treatmentprior to withdrawal. It was unexpectedly discovered that dexmedetomidineis effective at reducing the period of opioid withdrawal in an adultsubject. This is surprising because opioids (e.g. fentanyl) becomelocalized in body fat over time and are released intermittently and haveunpredictable effects on patients during the withdrawal process. Due tothe high degree of variability and intermittent release of opioids, aclinician would not expect repeated administration of dexmedetomidine tobe an effective therapy.

In some embodiments, the present disclosure provides a method ofpromoting non-rapid eye movement (non-REM) stage 3 sleep in a humansubject, comprising administering sublingually an effective amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof as asingle dose. In some embodiments, the human subject is hospitalized inICU with hyperactive delirium.

In some embodiments, the present disclosure provides a method oftreating cocaine toxicity and/or symptoms associated with cocainetoxicity comprising administering oromucosally an effective amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof. In someembodiments. In some embodiments, dexmedetomidine or a pharmaceuticallyacceptable salt thereof is administered as an oromucosal film at a doserange of about 30 μg to about 200 μg as a single dose or as a multi-dosetherapy.

In another embodiment (F), the present disclosure provides a method oftreating agitation or signs of agitation in a human subject withschizophrenia or bipolar disorder, without also inducing significantsedation, comprising administering an appropriate amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. thehydrochloride salt) resulting in a mean total exposure ofdexmedetomidine, as measured by plasma AUC from T0 to T∞, of about 3800ng*h/L. In some embodiments, the treatment is effective without causingclinically significant cardiovascular effects. In some embodiments, thedexmedetomidine is administered as a single dose. In some embodiments,the mean total exposure of dexmedetomidine, as measured by plasma AUCfrom T0 to T∞, is from about 80% to about 125% of 3800 ng*h/L. Forexample, the AUC is about 3024 ng*h/L, about 3100 ng*h/L, about 3200ng*h/L, about 3300 ng*h/L, about 3400 ng*h/L, about 3500 ng*h/L, about3600 ng*h/L, about 3700 ng*h/L, about 3800 ng*h/L, about 3900 ng*h/L,about 4000 ng*h/L, about 4100 ng*h/L, about 4200 ng*h/L, about 4300ng*h/L, about 4400 ng*h/L, about 4500 ng*h/L, about 4600 ng*h/L, orabout 4725 ng*h/L.

In another embodiment (G), the present disclosure provides a method oftreating agitation or signs of agitation in a human subject withschizophrenia or bipolar disorder, without also inducing significantsedation, comprising administering an appropriate amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. thehydrochloride salt) resulting in a mean total exposure ofdexmedetomidine, as measured by plasma AUC from T0 to T∞, of about 1800ng*h/L. In some embodiments, the treatment is effective without causingclinically significant cardiovascular effects. In some embodiments, thedexmedetomidine is administered as a single dose. In some embodiments,the mean total exposure of dexmedetomidine, as measured by plasma AUCfrom T₀ to T∞, is from about 80% to about 125% of 1800 ng*h/L. Forexample, the AUC is about 1440 ng*h/L, 1500 ng*h/L, about 1600 ng*h/L,about 1700 ng*h/L, about 1800 ng*h/L, about 1900 ng*h/L, about 2000ng*h/L, about 2100 ng*h/L, about 2200 ng*h/L, or about 2250 ng*h/L.

In a further embodiment (H), the present disclosure provides a method oftreating agitation or signs of agitation in a human subject withschizophrenia or bipolar disorder, without also inducing significantsedation, comprising administering an appropriate amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof resultingin a total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞, from about 600 to about 9500 ng*h/L. In some embodiments, thetreatment is effective without causing clinically significantcardiovascular effects. In some embodiments, the dexmedetomidine isadministered as a single dose. In some embodiments, the mean totalexposure of dexmedetomidine, as measured by plasma AUC from T0 to T∞, isfrom about 80% to about 125% of about 470 hr*ng/L, about 500 hr*ng/L,about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L,about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L,about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L,about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ng/L, about6000 hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L,about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, to about8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L,about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, or about 11875hr*ng/L.

In a further embodiment (I), the present disclosure provides a method oftreating agitation or signs of agitation in a human subject withschizophrenia or bipolar disorder, without also inducing significantsedation, comprising administering an appropriate amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof resultingin a total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞, from about 590. to about 4400 ng*h/L. In some embodiments, thetreatment is effective without causing clinically significantcardiovascular effects. In some embodiments, the dexmedetomidine isadministered as a single dose. In some embodiments, the mean totalexposure of dexmedetomidine, as measured by plasma AUC from T0 to T∞, isfrom about 80% to about 125% of about 470 hr*ng/L, about 500 hr*ng/L,about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L,about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L,about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L,about 5250 hr*ng/L, or about 5500 hr*ng/L.

In some embodiments of each of embodiments (A) to (I), dexmedetomidineor a pharmaceutically acceptable salt thereof may be administeredorally, oromucosally (e.g. sublingually, buccally), intravenously,intramuscularly, subcutaneously, topically, transdermally,intratracheally, intraperitoneally, intraorbitally, by implantation, byinhalation, intrathecally, intraventricularly or intranasally.

In some embodiments of each of embodiments (A) to (I), dexmedetomidineor a pharmaceutically acceptable salt thereof is administered to thesubject by the sublingual, buccal, oral, intranasal or parenteral route.In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered by the sublingual or buccal route. In someembodiments, dexmedetomidine or a pharmaceutically acceptable saltthereof is administered sublingually in the form of a tablet, film,spray, gel or drops, particularly a film. In some embodiments, the filmis placed under the tongue, close to the base of the tongue, on the leftor right side. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof is administered buccally in theform of a film, patch or tablet, particularly a film. In someembodiments, the film is placed against the inner lip or check, close tothe jaw line. In some embodiments, dexmedetomidine or a pharmaceuticallyacceptable salt thereof is administered parenterally to the subject inthe form of an intramuscular injection. In some embodiments,dexmedetomidine or a pharmaceutically acceptable salt thereof isadministered to the subject by oral route. In some embodiments,dexmedetomidine or a pharmaceutically acceptable salt thereof isadministered orally in the form of tablets, orally disintegratingtablets (ODTs), effervescent tablets, capsules, pellets, pills, lozengesor troches, powders, dispersible granules, catchets, aqueous solutions,syrups, emulsions, suspensions, solutions, soft gels, dispersions andthe like. In some embodiments, dexmedetomidine or a pharmaceuticallyacceptable salt thereof is administered orally to the subject in theform of an orally disintegrating tablet.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered sublingually to the subject as a singledose containing about 180 μg dexmedetomidine or a pharmaceuticallyacceptable salt thereof, wherein agitation or signs of agitation aretreated without also inducing clinically significant cardiovasculareffects. In some embodiments, agitation or signs of agitation is treatedwithout diastolic blood pressure falling below about 60 mmHg and/orwithout heart rate falling below about 50 beats per minute.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered sublingually to the subject as a singledose containing about 120 μg dexmedetomidine or a pharmaceuticallyacceptable salt thereof, wherein agitation or signs of agitation istreated without also inducing clinically significant cardiovasculareffects. In some embodiments, agitation or signs of agitation is treatedwithout systolic blood pressure falling below about 80 mmHg andor/without diastolic blood pressure falling below about 60 mmHg and/orwithout heart rate falling below about 50 beats per minute.

In certain embodiments, there is provided a method of treating agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of about 180 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about600 to about 9500 ng*h/L, wherein the plasma Tmax is about 1 to about 8hours. In some embodiments, the dexmedetomidine is administered as asingle dose. In some embodiments, the total exposure of dexmedetomidine,as measured by plasma AUC from T0 to T∞, is from about 80% to about 125%of about 600 to about 9500 ng*h/L. For example, about 470 hr*ng/L, about500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L,about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L,about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L,about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ng/L,about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, toabout 8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L,about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, or about 11875hr*ng/L. In some embodiments, the plasma Tmax from T0 to T∞, is fromabout 80% to about 125% of about 1 to about 8 hours. For example, about0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h,about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h,about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h,or about 10 h.

In certain embodiments, there is provided a method of treating agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of about 120 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about590 to about 4400 ng*h/L, wherein the plasma Tmax is about 1 to about 4hours. In some embodiments, the dexmedetomidine is administered as asingle dose. In some embodiments, the total exposure of dexmedetomidine,as measured by plasma AUC from T₀ to T∞, is from about 80% to about 125%of about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L,about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L,about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, or about5500 hr*ng/L. In some embodiments, the plasma T_(max) from T₀ to T∞, isfrom about 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h,about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h,about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about4.25 h, about 4.5 h, about 4.75 h, or about 5.0 h.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 180 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof sublingually to said subject, resulting in mean plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax from about 300 ng/L to about 500 ng/L (e.g. about400 ng/L) and AUC from T0 to T∞ of from about 2300 ng*h/L to about 3600ng*h/L (e.g. about 2900 ng*h/L). For example, the Cmax is about 240ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L,about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L, or about 625ng/L and the AUC0-inf is about 1840 hr*ng/L, about 2000 hr*ng/L, about2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L,about 4000 hr*ng/L, about 4250 hr*ng/L, or about 4500 hr*ng/L.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 120 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof sublingually to said subject, resulting in mean plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax from about 150 ng/L to about 350. ng/L (e.g.about 220 ng/L) and AUC from T0 to T∞ of from about 1100. ng*h/L toabout 1800 ng*h/L (e.g. about 1410 ng*h/L). For example, the Cmax isabout 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L,and the AUC0-inf is about 900 hr*ng/L, about 1000 hr*ng/L, about 1250hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, orabout 2250 hr*ng/L.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of about 180 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof to said subject, resulting ina mean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 3800 ng*h/L, wherein the mean plasma Cmax is about 400ng/L. In some embodiments, the plasma AUC from T0 to T∞ is from 80% toabout 125% of about 3800 ng*h/L, wherein the mean plasma Cmax is fromabout 80% to about 125% of about 400 ng/L.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of about 120 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof to said subject, resulting ina mean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 1800 ng*h/L, wherein the mean plasma Cmax is about 200ng/L. In some embodiments, the plasma AUC from T0 to T∞ is from 80% toabout 125% of about 1800 ng*h/L, wherein the mean plasma Cmax is fromabout 80% to about 125% of about 200 ng/L.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of about 180 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof to said subject, resulting ina mean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 3800 ng*h/L, wherein the median plasma Tmax is about 2hours. In some embodiments, the plasma AUC from T0 to T∞ is from 80% toabout 125% of about 3800 ng*h/L, wherein the median plasma Tmax is fromabout 80% to about 125% of about 2 hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of about 120 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof to said subject, resulting ina mean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 1800 ng*h/L, wherein the median plasma Tmax is about 2hours. In some embodiments, the plasma AUC from T0 to T∞ is from 80% toabout 125% of about 1800 ng*h/L, wherein the median plasma Tmax is fromabout 80% to about 125% of about 2 hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of about 180 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof to said subject resulting ina mean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 3800 ng*h/L, wherein the mean plasma Cmax is about 400ng/L and the median plasma Tmax is about 2 hours. In some embodiments,the plasma AUC from T0 to T∞ is from 80% to about 125% of about 3800ng*h/L, the mean plasma Cmax is from about 80% to about 125% of about400 ng/L, and the median plasma Tmax is from about 80% to about 125% ofabout 2 hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of about 120 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof to said subject resulting ina mean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 1800 ng*h/L, wherein the mean plasma Cmax is about 200ng/L and the median plasma Tmax is about 2 hours. In some embodiments,the plasma AUC from T0 to T∞ is from 80% to about 125% of about 1800ng*h/L, the mean plasma Cmax is from about 80% to about 125% of about200 ng/L, and the median plasma Tmax is from about 80% to about 125% ofabout 2 hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of about 180 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about600 to about 9500 ng*h/L, wherein the plasma Cmax is about 100 ng/L toabout 800 ng/L. In some embodiments, the plasma AUC from T0 to T∞ isfrom 80% to about 125% of about 600 ng*h/L to about 9500 ng*h/L and themean plasma Cmax is from about 80% to about 125% of about 100 ng/L toabout 800 ng/L.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of about 120 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about590 to about 4400 ng*h/L, wherein the plasma Cmax is about 110 ng/L toabout 400 ng/L. In some embodiments, the plasma AUC from T0 to T∞ isfrom 80% to about 125% of about 590 ng*h/L to about 4400 ng*h/L and themean plasma Cmax is from about 80% to about 125% of about 110 ng/L toabout 400 ng/L.

In certain embodiments, there is provided a method of treating agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of 180 μg of dexmedetomidine or apharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about600 to about 9500 ng*h/L, wherein the plasma Tmax is about 1 to about 8hours. In some embodiments, the plasma AUC from T0 to T∞ is from 80% toabout 125% of about 600 ng*h/L to about 9500 ng*h/L and the plasma Tmaxis from about 80% to about 125% of about 1 to about 8 hours.

In certain embodiments, there is provided a method of treating agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingsublingually administering a dose of 120 μg of dexmedetomidine or apharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about590 to about 4400 ng*h/L, wherein the plasma Tmax is about 1 to about 4.hours. In some embodiments, the plasma AUC from T0 to T∞ is from 80% toabout 125% of about 5900 ng*h/L to about 4400 ng*h/L and the plasma Tmaxis from about 80% to about 125% of about 1 to about 4 hours.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 180 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof sublingually to said subject, resulting in plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax from about 100 ng/L to about 800 ng/L and AUCfrom T0 to T∞ of about 600 hr*ng/L to about 9500 hr*ng/L.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 120 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof sublingually to said subject, resulting in plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax from about 110 ng/L to about 400 ng/L and AUCfrom T0 to T∞ of about 590 hr*ng/L to about 4400 hr*ng/L.

In certain embodiments, there is provided a method of treating acondition (e.g. agitation) in a human subject in need thereof, withoutalso inducing significant sedation, comprising administering an unitdose of 180 μg or 120 μg dexmedetomidine or a pharmaceuticallyacceptable salt thereof to said subject, resulting in rapid absorptionwith maximum concentration achieved on average within about 2.5 hoursafter administration.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering about 180μg of dexmedetomidine or a pharmaceutically acceptable salt thereofsublingually to said subject, resulting in plasma absorption levels ofdexmedetomidine from about 80% to about 125% of the following values:Cmax from about 100 ng/L to about 800 ng/L and AUC from T0 to T∞ ofabout 600 hr*ng/L to about 9500 hr*ng/L. In some embodiments, the plasmaTmax is about 1 hour to about 8 hours.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering about 120μg of dexmedetomidine or a pharmaceutically acceptable salt thereofsublingually to said subject, resulting in plasma absorption levels ofdexmedetomidine from about 80% to about 125% of the following values:Cmax from about 110 ng/L to about 400 ng/L and AUC from T0 to T∞ ofabout 590 hr*ng/L to about 4400 hr*ng/L. In some embodiments, the plasmaTmax is about 1 hour to about 4 hours.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 180 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof sublingually to said subject, resulting in mean plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax of from about 300 ng/L to about 500 ng/L (e.g.about 400 ng/L) and AUC from T0 to T∞ of from about 2300 ng*h/L. toabout 3600 ng*h/L (e.g. about 2900 ng*h/L), In some embodiments, theplasma Tmax is about 2 hours.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 120 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof sublingually to said subject, resulting in mean plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax of from about 150 ng/L to about 300 ng/L (e.g.about 220 ng/L) and AUC from T0 to T∞ of from about 1100 ng*h/L to about1800 ng*h/L (e.g. about 1400 ng*h/L). In some embodiments, the plasmaTmax is about 2 hours.

In certain embodiments, there is provided a method of treating agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of 180 μg of dexmedetomidine or apharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about600 to about 9500 ng*h/L, wherein the plasma Tmax is about 1 to about 8hours.

In certain embodiments, there is provided a method of treating agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of 120 μg of dexmedetomidine or apharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about590 to about 4400 ng*h/L, wherein the plasma Tmax is about 1 to about 4hours.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 180 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof buccally to said subject, resulting in mean plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax from about 300 ng/L to about 500 ng/L (e.g. about400 ng/L) and AUC from T0 to T∞ of from about 2300 ng*h/L to about 3600ng*h/L (e.g. about 2900 ng*h/L).

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 120 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof buccally to said subject, resulting in mean plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax from about 150 ng/L to about 300 ng/L (e.g. about220. ng/L) and AUC from T0 to T∞ of from about 1100 ng*h/L to about 1800ng*h/L (e.g. about 1400 ng*h/L).

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of about 180 μg of dexmedetomidine or apharmaceutically acceptable salt thereof to said subject, resulting in amean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 3800 ng*h/L, wherein the mean plasma Cmax is about 400ng/L.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of about 120 μg of dexmedetomidine or apharmaceutically acceptable salt thereof to said subject, resulting in amean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 1800 ng*h/L, wherein the mean plasma Cmax is about 200ng/L.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of about 180 μg of dexmedetomidine or apharmaceutically acceptable salt thereof to said subject, resulting in amean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 3780 ng*h/L, wherein the median plasma Tmax is about 2hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of about 120 μg of dexmedetomidine or apharmaceutically acceptable salt thereof to said subject, resulting in amean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 1800 ng*h/L, wherein the median plasma Tmax is about 2hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of about 180 μg of dexmedetomidine or apharmaceutically acceptable salt thereof to said subject resulting in amean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 3800 ng*h/L, wherein the mean plasma Cmax is about 400ng/L and the median plasma Tmax is about 2 hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of about 120 μg of dexmedetomidine or apharmaceutically acceptable salt thereof to said subject resulting in amean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞ of about 1800 ng*h/L, wherein the mean plasma Cmax is about 200ng/L and the median plasma Tmax is about 2 hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of about 180 μg of dexmedetomidine or apharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about600 to about 9500 ng*h/L, wherein the plasma Cmax is about 100 ng/L toabout 800 ng/L.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of about 120 μg of dexmedetomidine or apharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about590 to about 4400 ng*h/L, wherein the plasma Cmax is about 110 ng/L toabout 400 ng/L.

In certain embodiments, there is provided a method of treating agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of about 180 μg of dexmedetomidine or apharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about600 to about 9500 ng*h/L, wherein the plasma Tmax is about 1 to about 8hours.

In certain embodiments, there is provided a method of treating agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingbuccally administering a dose of about 120 μg of dexmedetomidine or apharmaceutically acceptable salt thereof resulting in a total exposureof dexmedetomidine, as measured by plasma AUC from T0 to T∞, from about590 to about 4400 ng*h/L, wherein the plasma Tmax is about 1 to about 4hours.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 180 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof buccally to said subject, resulting in plasma absorptionlevels of dexmedetomidine from about 80% to about 125% of the followingvalues: Cmax from about 100 ng/L to about 800 ng/L and AUC from T0 to T∞of about 600 hr*ng/L to about 9500 hr*ng/L.

In some embodiments, there is provided a method of treating a conditionin a human subject, comprising administering to said subject about 120μg of dexmedetomidine or a pharmaceutically acceptable salt thereofbuccally to said subject, resulting in plasma absorption levels ofdexmedetomidine from about 80% to about 125% of the following values:Cmax from about 110 ng/L to about 400 ng/L and AUC from T0 to T∞ ofabout 590 hr*ng/L to about 4400 hr*ng/L.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering about 180μg of dexmedetomidine or a pharmaceutically acceptable salt thereofbuccally to said subject, resulting in plasma absorption levels ofdexmedetomidine from about 80% to about 125% of the following values:Cmax from about 100 ng/L to about 800 ng/L and AUC from T0 to T∞ ofabout 600 hr*ng/L to about 9500 hr*ng/, wherein the plasma Tmax is about1 hour to about 8 hours.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering about 120μg of dexmedetomidine or a pharmaceutically acceptable salt thereofbuccally to said subject, resulting in plasma absorption levels ofdexmedetomidine from about 80% to about 125% of the following values:Cmax from about 110 ng/L to about 400 ng/L and AUC from T0 to T∞ ofabout 590 hr*ng/L to about 4400 hr*ng/L, wherein the plasma Tmax isabout 1 hour to about 4 hours.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 180 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof buccally to said subject, resulting in mean plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax of from about 300 ng/L to about 500 ng/L (e.g.about 400 ng/L) and AUC from T0 to T∞ of from about 2300 ng*h/L to about3600 ng*h/L (e.g. about 2900 ng*h/L), wherein the median plasma Tmax isabout 2 hours.

In some embodiments, there is provided a method of treating a condition(e.g. agitation) in a human subject, comprising administering to saidsubject about 120 μg of dexmedetomidine or a pharmaceutically acceptablesalt thereof buccally to said subject, resulting in mean plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax of from about 150 ng/L to about 300 ng/L (e.g.about 200 ng/L) and AUC from T0 to T∞ of from about 1100 ng*h/L to about1800 ng*h/L (e.g. about 1400 ng*h/L), wherein the median plasma Tmax isabout 2 hours.

In certain embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered parenterally to the subject in the form ofan intramuscular injection, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered at a dose ofabout 140 μg to about 190 μg.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingintramuscularly administering a dose of about 120 μg to about 190 μg ofdexmedetomidine or a pharmaceutically acceptable salt thereof resultingin a total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞, from about 600 to about 9500 ng*h/L, wherein the plasma Tmaxis about 5 minutes to about 4 hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingintramuscularly administering a dose of about 120 μg to about 190 μg ofdexmedetomidine or a pharmaceutically acceptable salt thereof resultingin a total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞, from about 600 to about 12600 ng*h/L, wherein the plasma Tmaxis about 5 minutes to about 4 hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingintramuscularly administering a dose of about 120 μg to about 190 μg ofdexmedetomidine or a pharmaceutically acceptable salt thereof resultingin a total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞, from about 600 to about 12600 ng*h/L, wherein the plasma Cmaxis about 200 to about 800 ng/L.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingintramuscularly administering a dose of about 120 μg to about 190 μg ofdexmedetomidine or a pharmaceutically acceptable salt thereof resultingin a total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞, from about 600 to about 12600 ng*h/L, wherein the median Tmaxis about 2 hours.

In some embodiments, there is provided a method of treating agitation orsigns of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprisingintravenously administering a dose of about 120 μg to about 190 μg ofdexmedetomidine or a pharmaceutically acceptable salt thereof resultingin a total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞, from about 600 to about 12600 ng*h/L, wherein the plasma Tmaxis about 5 minutes to about 15 minutes.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered orally to the subject, whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered at a dose of about 900 μg to about 1200 μg.

In certain embodiments, there is provided a method of treating agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprising orallyadministering a dose of about 900 μg to about 1200 μg of dexmedetomidineor a pharmaceutically acceptable salt thereof resulting in a totalexposure of dexmedetomidine, as measured by plasma AUC from T0 to T∞,from about 600 to about 12600 ng*h/L, wherein the plasma Tmax is about 1hour to about 8 hours.

In certain embodiments, there is provided a method of treating agitationor signs of agitation in a human subject with schizophrenia or bipolardisorder, without also inducing significant sedation, comprising orallyadministering a dose of about 900 μg to about 1200 μg of dexmedetomidineor a pharmaceutically acceptable salt thereof resulting in a totalexposure of dexmedetomidine, as measured by plasma AUC from T0 to T∞,from about 600 to about 12600 ng*h/L, wherein the median Tmax is about 2hours.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered as a single dose (e.g. as a single unitdose or multiple unit doses administered simultaneously).

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising about 180 μg of dexmedetomidinehydrochloride, wherein application of said film sublingually to asubject with schizophrenia or bipolar disorder results in plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax from about 100 ng/L to about 800 ng/L and AUCfrom T0 to T∞ of about 600 hr*ng/L to about 9500 hr*ng/L.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising about 120 μg of dexmedetomidinehydrochloride, wherein application of said film sublingually to asubject with schizophrenia or bipolar disorder results in plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax from about 110 ng/L to about 400 ng/L and AUCfrom T0 to T∞ of about 590 hr*ng/L to about 4400 hr*ng/L.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising about 180 μg of dexmedetomidinehydrochloride, wherein application of said film sublingually to asubject with schizophrenia or bipolar disorder results in plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax from about 300 ng/L to about 500 ng/L (e.g. about400 ng/L) and AUC from T0 to T∞ of about 2300 ng*h/L to about 3600ng*h/L (e.g. about 2900 ng*h/L), wherein the median plasma Tmax is about2 hours.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising about 120 μg of dexmedetomidinehydrochloride, wherein application of said film sublingually to asubject with schizophrenia or bipolar disorder results in plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax from about 150 ng/L to about 300. ng/L (e.g.about 200 ng/L) and AUC from T0 to T∞ of about 1100 ng*h/L. to about1800 ng*h/L (e.g. about 1400 ng*h/L), wherein the median plasma Tmax isabout 2 hours.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising about 180 μg to about 240 μg ofdexmedetomidine hydrochloride, wherein application of said filmsublingually to a subject with schizophrenia or bipolar disorder resultsin a total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞, from about 600 to about 12600 ng*h/L, wherein the plasma Tmaxis about 1 to about 8 hours.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising:

-   -   (a) a composition consisting essentially of:    -   (i) about 180 μg of dexmedetomidine hydrochloride;    -   (ii) hydroxypropyl cellulose (40,000 MW); and    -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:    -   (i) hydroxypropyl cellulose (40,000 MW);    -   (ii) hydroxypropyl cellulose (140,000 MW);    -   (iii) hydroxypropyl cellulose (370,000 MW); and    -   (iv) polyethylene oxide (600,000 MW);        wherein the composition of part (a) is present on the surface of        the film substrate (b), and wherein application of said film        sublingually to a subject with schizophrenia or bipolar disorder        results in plasma absorption levels of dexmedetomidine from        about 80% to about 125% of the following values: Cmax from about        100 ng/L to about 800 ng/L and AUC from T₀ to T∞ of about 600        hr*ng/L to about 9500 hr*ng/L. For example, the Cmax is about 80        ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175        ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275        ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375        ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475        ng/L, about 500 ng/L, about 525 ng/L, about 550 ng/L, about 575        ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675        ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775        ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875        ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975        ng/L, to about 1000 ng/L, and the AUC_(0-inf) is about 470        hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700        hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000        hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750        hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500        hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250        hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000        hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750        hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, about 5500        hr*ng/L, about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250        hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng/L, about 7000        hr*ng/L, about 7250 hr*ng/L, about 7500 hr*ng/L, about 7750        hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, about 8500        hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250        hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000        hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750        hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500        hr*ng/L, to about 11875 hr*ng/L. In some embodiments, the Tmax        is from about 1 to about 8 hours. For example, the Tmax is about        0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about        1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h,        about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0        h, about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about        5.25 h, about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 h,        about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5        h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about        8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, to        about 10 h.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising:

-   -   (a) a composition consisting essentially of:    -   (i) about 120 μg of dexmedetomidine hydrochloride;    -   (ii) hydroxypropyl cellulose (40,000 MW); and    -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:    -   (i) hydroxypropyl cellulose (40,000 MW);    -   (ii) hydroxypropyl cellulose (140,000 MW);    -   (iii) hydroxypropyl cellulose (370,000 MW); and    -   (iv) polyethylene oxide (600,000 MW);        wherein the composition of part (a) is present on the surface of        the film substrate (b), and wherein application of said film        sublingually to a subject with schizophrenia or bipolar disorder        results in plasma absorption levels of dexmedetomidine from        about 80% to about 125% of the following values: Cmax from about        110 ng/L to about 400 ng/L and AUC from T₀ to T∞ of about 590        hr*ng/L to about 4400 hr*ng/L. For example, the Cmax is about 80        ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175        ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275        ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375        ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475        ng/L, to about 500 ng/L, and the AUC_(0-inf) is about 470        hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700        hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000        hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750        hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500        hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250        hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000        hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750        hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500        hr*ng/L. In some embodiments, the Tmax is from about 1 to about        4 hours. For example, the Tmax is about 0.8 h, about 0.9 h,        about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h,        about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25        h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about        4.5 h, about 4.75 h, to about 5.0 h.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising:

-   -   (a) a composition consisting essentially of:    -   (i) about 180 μg of dexmedetomidine hydrochloride;    -   (ii) hydroxypropyl cellulose (40,000 MW); and    -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:    -   (i) hydroxypropyl cellulose (40,000 MW);    -   (ii) hydroxypropyl cellulose (140,000 MW);    -   (iii) hydroxypropyl cellulose (370,000 MW); and    -   (iv) polyethylene oxide (600,000 MW);        wherein the composition of part (a) is present on the surface of        the film substrate (b), and wherein application of said film        sublingually to a subject with schizophrenia or bipolar disorder        results in plasma absorption levels of dexmedetomidine from        about 80% to about 125% of the following values: Cmax from about        100 ng/L to about 800 ng/L and AUC from T₀ to T∞ of about 600        hr*ng/L to about 9500 hr*ng/L, wherein the plasma Tmax is about        1 hour to about 8 hours. For example, the Cmax is about 80 ng/L,        about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L,        about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L,        about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L,        about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L,        about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L,        about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L,        about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L,        about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L,        about 975 ng/L, to about 1000 ng/L, and the AUC_(0-inf) is about        470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700        hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000        hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750        hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500        hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250        hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000        hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750        hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500        hr*ng/L, about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250        hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng/L, about 7000        hr*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750        hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, to about 8500        hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250        hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000        hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750        hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500        hr*ng/L, to about 11875 hr*ng/L, and the Tmax is about 0.8 h,        about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h,        about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0        h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about        4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h,        about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 h, about 6.5        h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5 h, about        7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h,        about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, to about        10 h.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising:

-   -   (a) a composition consisting essentially of:    -   (i) about 120 μg of dexmedetomidine hydrochloride;    -   (ii) hydroxypropyl cellulose (40,000 MW); and    -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:    -   (i) hydroxypropyl cellulose (40,000 MW);    -   (ii) hydroxypropyl cellulose (140,000 MW);    -   (iii) hydroxypropyl cellulose (370,000 MW); and    -   (iv) polyethylene oxide (600,000 MW);        wherein the composition of part (a) is present on the surface of        the film substrate (b), and wherein application of said film        sublingually to a subject with schizophrenia or bipolar disorder        results in plasma absorption levels of dexmedetomidine from        about 80% to about 125% of the following values: Cmax from about        110 ng/L to about 400 ng/L and AUC from T₀ to T∞ of about 590        hr*ng/L to about 4400 hr*n/L, wherein the plasma Tmax is about 1        hour to about 4 hours. For example, the Cmax is about 80 ng/L,        about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L,        about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L,        about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L,        about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, to        about 500 ng/L, and the AUC_(0-inf) is about 470 hr*ng/L, about        500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800        hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250        hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000        hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750        hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500        hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250        hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000        hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, and the Tmax        is about 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5        h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about        2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h,        about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, to about        5.0 h.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising:

-   -   (a) a composition consisting essentially of:    -   (i) about 180 μg of dexmedetomidine hydrochloride;    -   (ii) hydroxypropyl cellulose (40,000 MW); and    -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:    -   (i) hydroxypropyl cellulose (40,000 MW);    -   (ii) hydroxypropyl cellulose (140,000 MW);    -   (iii) hydroxypropyl cellulose (370,000 MW); and    -   (iv) polyethylene oxide (600,000 MW);        wherein the composition of part (a) is present on the surface of        the film substrate (b), and wherein application of said film        sublingually to a subject with schizophrenia or bipolar disorder        results in mean plasma absorption levels of dexmedetomidine from        about 80% to about 125% of the following values: Cmax of about        300 ng/L to about 474 ng/L (e.g. about 400 ng/L) and AUC from T₀        to T∞ of about 2300 ng*h/L. to about 3600 ng*h/L (e.g. about        2900 ng*h/L), wherein the median plasma Tmax is about 2 hours.        For example, the Cmax is about 300 ng/L, about 325 ng/L, about        350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about        450 ng/L, to about 475 ng/L, and the AUC_(0-inf) is about 2250        hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000        hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750        hr*ng/L. In some embodiments, the Tmax is from about 1 to about        4 hours. For example, the Tmax is about 0.8 h, about 0.9 h,        about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h,        about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25        h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about        4.5 h, about 4.75 h, to about 5.0 h.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising:

-   -   (a) a composition consisting essentially of:    -   (i) about 120 μg of dexmedetomidine hydrochloride;    -   (ii) hydroxypropyl cellulose (40,000 MW); and    -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:    -   (i) hydroxypropyl cellulose (40,000 MW);    -   (ii) hydroxypropyl cellulose (140,000 MW);    -   (iii) hydroxypropyl cellulose (370,000 MW); and    -   (iv) polyethylene oxide (600,000 MW);        wherein the composition of part (a) is present on the surface of        the film substrate (b), and wherein application of said film        sublingually to a subject with schizophrenia or bipolar disorder        results in mean plasma absorption levels of dexmedetomidine from        about 80% to about 125% of the following values: Cmax of about        150 ng/L to about 300 ng/L (e.g. about 200 ng/L) and AUC from T₀        to T∞ of about 1100 ng*h/L. to about 1800 ng*h/L (e.g. about        1400 ng*h/L), wherein the median plasma Tmax is about 2 hours.        For example, the Cmax is about 150 ng/L, about 175 ng/L, about        200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, or        about 300 ng/L, and the AUC_(0-inf) of is about 1100 hr*ng/L,        about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, to        about 1800 hr*ng/L. In some embodiments, the Tmax is from about        1 to about 4 hours. For example, the Tmax is about 0.8 h, about        0.9 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about        2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h,        about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25        h, about 4.5 h, about 4.75 h, to about 5.0 h

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising:

-   -   (a) a composition consisting essentially of:    -   (i) about 180 μg of dexmedetomidine hydrochloride;    -   (ii) hydroxypropyl cellulose (40,000 MW); and    -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:    -   (i) hydroxypropyl cellulose (40,000 MW);    -   (ii) hydroxypropyl cellulose (140,000 MW);    -   (iii) hydroxypropyl cellulose (370,000 MW); and    -   (iv) polyethylene oxide (600,000 MW);        wherein the composition of part (a) is present on the surface of        the film substrate (b), and wherein application of said film        sublingually to a subject with schizophrenia or bipolar disorder        results in a total exposure of dexmedetomidine, as measured by        plasma AUC from T₀ to T∞, from about 600 to about 12600 ng*h/L,        wherein the plasma Tmax is about 1 to about 8 hours. For        example, the AUC_(0-inf) is about 470 hr*ng/L, about 500        hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800        hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250        hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000        hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750        hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500        hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250        hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000        hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750        hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500        hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250        hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000        hr*ng/L, about 8250 hr*ng/L, to about 8500 hr*ng/L, about 8750        hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500        hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250        hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000        hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, about 11750        hr*ng/L, about 12000 hr*ng/L, about 12250 hr*ng/L, or about        12600 hr*ng/L, and the Tmax is about 1 h, about 2 h, about 3 h,        about 4 h, about 5 h, about 6 h, about 7 h, or about 8 h.

Another embodiment of the present disclosure provides a self-supporting,dissolvable, film comprising:

-   -   (a) a composition consisting essentially of:    -   (i) about 120 μg of dexmedetomidine hydrochloride;    -   (ii) hydroxypropyl cellulose (40,000 MW); and    -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:    -   (i) hydroxypropyl cellulose (40,000 MW);    -   (ii) hydroxypropyl cellulose (140,000 MW);    -   (iii) hydroxypropyl cellulose (370,000 MW); and    -   (iv) polyethylene oxide (600,000 MW);        wherein the composition of part (a) is present on the surface of        the film substrate (b), and wherein application of said film        sublingually to a subject with schizophrenia or bipolar disorder        results in a total exposure of dexmedetomidine, as measured by        plasma AUC from T₀ to T∞, from about 590 to about 8750 ng*h/L,        wherein the plasma Tmax is about 1 to about 4 hours. For        example, the AUC_(0-inf) is about 590 hr*ng/L, about 600        hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900        hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500        hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250        hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000        hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750        hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500        hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250        hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ng/L, about 6000        hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750        hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500        hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250        hr*ng/L, about 8500 hr*ng/L, or about 8750 hr*ng/L, and the Tmax        is about 1 h, about 2 h, about 3 h, or about 4 h.

In some embodiments, agitation or signs of agitation are significantlyreduced within 60 minutes in a patient with schizophrenia or bipolardisorder following administration of a single dose of 120 μg or 180 μgof dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g.dexmedetomidine hydrochloride, as measured by the relative PEC scoresjust prior to and 60 minutes after administering dexmedetomidine or apharmaceutically acceptable salt thereof.

In some embodiments, the relative PEC scores are different by at leastsix points. In another embodiment, the relative PEC scores are differentby at least eight points. In yet another embodiment, the difference inrelative PEC scores is maintained for at least six hours. In aparticular embodiment, a difference of at least eight points ismaintained for up to about 24 hours when administering a single dose of180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof(e.g. dexmedetomidine hydrochloride).

In some embodiments, the decrease in PEC score at 2 hours, as measuredby change from baseline total PEC score post-administration of 180 μg ofdexmedetomidine hydrochloride is −10.8 compared to placebo (−4.5). Insome embodiments, the decrease in PEC score at 2 hourspost-administration of 180 μg of dexmedetomidine hydrochloride isgreater (−10.8) as compared to administering 120 μg (−9.2) or 80 μg(−7.3) dexmedetomidine hydrochloride. In some embodiments,dexmedetomidine or a pharmaceutically acceptable salt thereof isadministered immediately prior to or immediately following theappearance of agitation or signs of agitation in the human subject.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered within 10 minutes following the appearanceof agitation or signs of agitation in the human subject. In someembodiments, an additional dose of 90 μg or 60 μg may be taken after asuitable period of time (e.g. two hours) of first dosing.

In some embodiments, following administering a unit dose of about 30 μg,about 60 μg, about 90 μg, about 120 μg, or about 180 μg ofdexmedetomidine or a pharmaceutically acceptable thereof in a humansubject experiencing opioid withdrawal symptoms (e.g. agitation or signsof agitation), the withdrawal symptoms are significantly reduced asmeasured by the relative COWS and/or the SOWS-Gossop scores just priorto and 2 hour post administration of dexmedetomidine or apharmaceutically acceptable salt thereof. In a particular embodiment,each unit may be administered twice daily over an appropriate period ofwithdrawal (e.g. for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14days).

In certain embodiments, following administering of about 20 μg to about240 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof(e.g. dexmedetomidine hydrochloride) to an agitated human subject withdelirium hospitalized (e.g. in an ICU), the agitation or signs ofagitation and delirium severity are significantly reduced as measured bythe RASS and DRS-R-98 respectively. For example, the agitation or signsof agitation and delirium severity are significantly reduced as measuredby the RASS and DRS-R-98 just prior to and after every 30 minutes, 1hour, 2 hours, 3, hours, 4 hours, 5 hours, or 6 hourspost-administration of dexmedetomidine. In some embodiments,dexmedetomidine is oromucosally (e.g. sublingually or buccally)administered one to four times a day at an appropriate dosing interval(e.g. after every 30 minutes) within 6 hours of first dose to produce adesired effect; for example, a 20 μg unit dose is administered fourtimes at a dosing interval of 30 minutes within 6 hours of first dose toproduce the effect of a 80 μg dose or a 60 μg unit dose is administeredfour times at a dosing interval of 30 minutes within 6 hours of firstdose to produce the effect of a 240 μg.

In some embodiments, following administration of about 30 μg to about 90μg of dexmedetomidine or a pharmaceutically acceptable salt thereof(e.g. dexmedetomidine hydrochloride) to an agitated human subject withdementia, the agitation or signs of agitation are significantly reducedas measured by the PAS and PEC. For example, the agitation or signs ofagitation are significantly reduced as measured by the PAS and PEC justprior to and after every 2 hours up to at least 24 hours postadministration of dexmedetomidine or a pharmaceutically acceptable saltthereof. In one embodiment, dexmedetomidine is oromucosally (e.g.sublingually or buccally) administered. In some embodiments, each unitdose comprises about 30 μg to 60 μg of dexmedetomidine or apharmaceutically acceptable salt thereof. In some embodiments, a dose ofdexmedetomidine may be taken 1, 2, 3, 4, 5, or 6 times in a day every 2hours with the provision of maximum of three doses within 12 hours offirst dose. In some embodiments, each unit dose containing about 90 μgof dexmedetomidine or a pharmaceutically acceptable salt thereof may betaken 1, 2, 3, or 4 times in a day at every 2 hours with the provisionof maximum of two doses within 12 hours of first dose.

In some embodiments, dexmedetomidine or a pharmaceutically acceptablesalt thereof is administered oromucosally (e.g. sublingually orbuccally) as a film. In some embodiments, the dosing may be achieved bycutting the film into half to deliver a half-dose (for e.g. 60 μg dosemay be administered with a half of a 60 μg dose (30 μg) to make a 90 μgdose.).

In some embodiments, the present disclosure provides a method oftreating agitation associated with schizophrenia or bipolar disorder,comprising administering a unit dose composition comprising about 120 μgof dexmedetomidine (e.g. dexmedetomidine hydrochloride) or apharmaceutically acceptable salt thereof to a human patient. Forexample, in some embodiments, the patient has schizophrenia, in someembodiments, the patient has bipolar disorder (E.g. bipolar I disorder,and in some embodiments, the patient has both schizophrenia and bipolardisorder (e.g. bipolar I disorder).

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, the composition may be administered a variety ofmeans. For example, in some embodiments, the composition comprisingdexmedetomidine (e.g. dexmedetomidine hydrochloride) or apharmaceutically acceptable salt is administered sublingually, buccally,orally, intranasally or parenterally. In some embodiments, thecomposition is administered sublingually or buccally. In someembodiments, the composition is administered sublingually in the form ofa tablet, film, spray, gel or drops. In some embodiments, thecomposition is administered buccally in the form of a film, patch ortablet.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, the method may further comprises administering asecond dose of dexmedetomidine after a period of time ranging from about30 minutes to about 12 hours. For example, the period of time may beabout 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours,or about 23 hours. In some embodiments, the second dose is administeredafter a period of about 2 hours. In some embodiments, the second doseranges from about 10 μg to about 180 μg. For example, the additionaldose may be about 10 about 20 about 30 about 40 about 50 about 60 about70 about 80 about 90 about 100 μg, about 110 about 120 about 130 about140 about 150 about 160 about 170, or about 180 μg. In some embodiments,the additional dose is about 60 μg or 90 μg.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, the unit dose composition may be administered to apatient in the fasted state. In some embodiments, the unit dosecomposition has been administered in the fed state.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, agitation is significantly reduced within about 2hours of administering the composition, as measured by a mean change inPositive and Negative Syndrome Scale Excited Component (PEC) scoresrelative to baseline. In some embodiments, the agitation issignificantly reduced within about 45 minutes to about 1 hour. In someembodiments, the agitation is significantly reduced in less than 45minutes (e.g. about 15 minutes, about 20 minutes, about 25 minutes,about 30 minutes). In some embodiments, the patient experiences ≥40%decrease from baseline in PEC score. For example, the patient mayexperience greater than or equal to about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, about 95%, about 100%, about 105%, about 110%, about115%, about 120%, about 125%, about 130%, about 135%, about 140%, about145%, or about 150% from baseline. Treatment efficacy may also becompared by comparing PEC score to placebo. In some embodiments, the PECscore is ≥30% lower than placebo (e.g. the placebo group has mean changefrom baseline in PEC total score of −3 and thedexmedetomidine-containing composition has a score of −3.9). Forexample, compared to placebo, the patient's PEC score may be lower bygreater than or equal to about 30,%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 100%, about 105%, about110%, about 115%, about 120%, about 125%, about 130%, about 135%, about140%, about 145%, about 150%, about 155%, about 160%, about 165%, about170%, about 175%, about 180%, about 185%, about 190%, about 195%, orabout 200%. In some embodiments, the patient experiences a mean changein PEC score of greater than about −4 (i.e. a decrease of 4 or morepoints) relative to baseline within 2 hours of administering thecomposition. For example, at the 2 hour time point, the patient mayexperience a mean change in PEC score of greater than about −4, about−5, about −6, about −7, about −8, about −9, about −10, about −11, orabout −12. In some embodiments, the decrease in PEC score (e.g. ofgreater than about −4) is maintained for at least six hours followingadministration of the composition. For example, if a patient experiencesa mean change from baseline in PEC total score of e.g. −6 at 2 hours,then at 6 hours patient's mean change in PEC score will be about −6 orlower (e.g. −7, −8, etc.). In some embodiments, the decrease in PECscore (e.g. of greater than about −4) is substantially maintained for atleast six hours following administration of the composition. Forexample, if a patient experiences a mean change from baseline in PECtotal score of e.g. −6 at 2 hours, then at 6 hours patient's mean changein PEC score will be about −4, about −5, or about −6 or lower (e.g. −7,−8, etc.). In some embodiments, the mean change in PEC score is greaterthan or equal to −8 and is maintained from 2 hours post administrationup to at least about 6 hours following administration of thecomposition.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, the subject is treated without experiencingsignificant sedation. In some embodiments, the subject is treatedwithout experiencing clinically significant cardiovascular effects.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, administration of a single dose provides a meanC_(max) within the range of about 80% to about 125% of about 110 ng/L toabout 400 ng/L. For example, a single dose provides a mean C_(max) ofabout 88 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L about 175ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L,about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, or about 500ng/L, including all integers and ranges therebetween. In someembodiments, the mean C_(max) is between about 100 ng/L to about 500ng/L, about 150 ng/L to about 450 ng/L, about 150 ng/L to about 400ng/L, about 200 ng/L to about 350 ng/L, about 200 ng/L to about 300ng/L, about 200 ng/L to about 250 mg/L, or about 210 ng/L to about 240ng/L. In some embodiments, the mean C_(max) is within the range of about80% to about 125% of about 238 ng/L. the mean C_(max) is within therange of about 80% to about 125% of about 238 ng/L. In some embodiments,the mean C_(max) is about 238 ng/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, administration of a single dose provides a meanAUC_(0-inf) within the range of about 80% to about 125% of about 590hr*ng/L to about 4400 hr*ng/L. For example, a single dose provides amean AUC_(0-inf) of about 475 hr*ng/L, about 500 hr*ng/L, about 1000hr*ng/L, about 1500 hr*ng/L, about 2000 hr*ng/L, about 2500 hr*ng/L,about 3000 hr*ng/L, about 3500 hr*ng/L, about 4000 hr*ng/L, about 4500hr*ng/L, about 5000 hr*ng/L, or about 5500 hr*ng/L, including allintegers and ranges therebetween. In some embodiments, the meanAUC_(0-inf) is between about 500 hr*ng/L to about 5000 hr*ng/L, about500 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about 3000hr*ng/L, about 1000 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L toabout 2500 hr*ng/L, about 1000 hr*ng/L to about 2000 hr*ng/L, about 1000hr*ng/L to about 1500 hr*ng/L, or about 1500 hr*ng/L to about 2000hr*ng/L. In some embodiments, the mean AUC_(0-inf) is within the rangeof about 80% to about 125% of about 1800 ng*h/L. In some embodiments,the mean AUC_(0-inf) is about 1800 ng*h/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, administration of a single dose provides a meanT_(max) within the range of about 80% to about 125% of about 1 hour toabout 4 hours. For example, a single dose provides a mean T_(max) ofabout 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h,about 4.5 h, about 4.75 h, to about 5.0 h. In some embodiments, theT_(max) is between about 1 h to about 4 h, about 1 h to about 3 h, about1.5 h to about 3 h, about 1.75 h to about 2.5 h, about 1.75 h to about2.25 h. In some embodiments, the T_(max) is within the range of about80% to about 125% of about 2 hours. In some embodiments, the T_(max) isabout 2 hours.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, administration of a single dose provides a geometricmean C_(max) within the range of about 80% to about 125% of about 110ng/L to about 400 ng/L. For example, a single dose provides a geometricmean C_(max) of about 88 ng/L, about 100 ng/L, about 125 ng/L, about 150ng/L about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L,about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475ng/L, or about 500 ng/L, including all integers and ranges therebetween.In some embodiments, the geometric mean C_(max) is between about 100ng/L to about 500 ng/L, about 150 ng/L to about 450 ng/L, about 150 ng/Lto about 400 ng/L, about 200 ng/L to about 350 ng/L, about 200 ng/L toabout 300 ng/L, about 200 ng/L to about 250 mg/L, or about 210 ng/L toabout 240 ng/L. In some embodiments, the geometric mean C_(max) iswithin the range of about 80% to about 125% of about 220 ng/L. In someembodiments, the geometric mean C_(max) is about 220 ng/L. In someembodiments, the median C_(max) is about 238 ng/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, administration of a single dose provides a geometricmean AUC_(0-inf) within the range of about 80% to about 125% of about590 hr*ng/L to about 4400 hr*ng/L. For example, a single dose provides ageometric mean AUC_(0-inf) of about 475 hr*ng/L, about 500 hr*ng/L,about 1000 hr*ng/L, about 1500 hr*ng/L, about 2000 hr*ng/L, about 2500hr*ng/L, about 3000 hr*ng/L, about 3500 hr*ng/L, about 4000 hr*ng/L,about 4500 hr*ng/L, about 5000 hr*ng/L, or about 5500 hr*ng/L, includingall integers and ranges therebetween. In some embodiments, the geometricmean AUC_(0-inf) is between about 500 hr*ng/L to about 5000 hr*ng/L,about 500 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about 3000hr*ng/L, about 1000 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L toabout 2500 hr*ng/L, about 1000 hr*ng/L to about 2000 hr*ng/L, about 1000hr*ng/L to about 1500 hr*ng/L, about 1500 hr*ng/L to about 2000 hr*ng/L,about 1200 hr*ng/L to about 1500 hr*ng/L, about 1300 hr*ng/L to about1500 hr*ng/L, or about 1350 hr*ng/L to about 1450 hr*ng/L. In someembodiments, the geometric mean AUC_(0-inf) is within the range of about80% to about 125% of about 1410 ng*h/L. In some embodiments, thegeometric mean AUC_(0-inf) is about 1410 ng*h/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, administration of a single dose provides a geometricmean T_(max) within the range of about 80% to about 125% of about 1 hourto about 4 hours. For example, a single dose provides a geometric meanT_(max) of about 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h,about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about4.25 h, about 4.5 h, about 4.75 h, to about 5.0 h. In some embodiments,the geometric mean T_(max) is between about 1 h to about 4 h, about 1 hto about 3 h, about 1.5 h to about 3 h, about 1.75 h to about 2.5 h,about 1.75 h to about 2.25 h. In some embodiments, the T_(max) is withinthe range of about 80% to about 125% of about 2 hours. In someembodiments, the T_(max) is about 2 hours.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, administration of a single dose provides a medianC_(max) within the range of about 80% to about 125% of about 110 ng/L toabout 400 ng/L. For example, a single dose provides a median C_(max) ofabout 88 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L about 175ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L,about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, or about 500ng/L, including all integers and ranges therebetween. In someembodiments, the mean median C_(max) is between about 100 ng/L to about500 ng/L, about 150 ng/L to about 450 ng/L, about 150 ng/L to about 400ng/L, about 200 ng/L to about 350 ng/L, about 200 ng/L to about 300ng/L, about 200 ng/L to about 250 mg/L, or about 210 ng/L to about 240ng/L. In some embodiments, the median C_(max) is within the range ofabout 80% to about 125% of about 230 ng/L. In some embodiments, themedian C_(max) is about 230 ng/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, administration of a single dose provides a medianAUC_(0-inf) within the range of about 80% to about 125% of about 590hr*ng/L to about 4400 hr*ng/L. For example, a single dose provides amedian AUC_(0-inf) of about 475 hr*ng/L, about 500 hr*ng/L, about 1000hr*ng/L, about 1500 hr*ng/L, about 2000 hr*ng/L, about 2500 hr*ng/L,about 3000 hr*ng/L, about 3500 hr*ng/L, about 4000 hr*ng/L, about 4500hr*ng/L, about 5000 hr*ng/L, or about 5500 hr*ng/L, including allintegers and ranges therebetween. In some embodiments, the medianAUC_(0-inf) is between about 500 hr*ng/L to about 5000 hr*ng/L, about500 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about 3000hr*ng/L, about 1000 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L toabout 2500 hr*ng/L, about 1000 hr*ng/L to about 2000 hr*ng/L, about 1000hr*ng/L to about 1500 hr*ng/L, about 1500 hr*ng/L to about 2000 hr*ng/L,about 1000 hr*ng/L to about 1250 hr*ng/L, about 1000 hr*ng/L to about1200 hr*ng/L, about 1100 hr*ng/L to about 1200 hr*ng/L, or about 1150hr*ng/L to about 1250 hr*ng/L. In some embodiments, the medianAUC_(0-inf) is within the range of about 80% to about 125% of about 1180ng*h/L. In some embodiments, the median AUC_(0-inf) is about 1180ng*h/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, administration of a single dose provides a medianT_(max) within the range of about 80% to about 125% of about 1 hour toabout 4 hours. For example, a single dose provides a median T_(max) ofabout 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h,about 4.5 h, about 4.75 h, to about 5.0 h. In some embodiments, themedian T_(max) is between about 1 h to about 4 h, about 1 h to about 3h, about 1.5 h to about 3 h, about 1.75 h to about 2.5 h, about 1.75 hto about 2.25 h. In some embodiments, the median T_(max) is within therange of about 80% to about 125% of about 2 hours. In some embodiments,the median T_(max) is about 2 hours.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgof dexmedetomidine, the aforementioned pharmacokinetic parameters arenon-steady state.

In some embodiments, the present disclosure provides a method oftreating agitation associated with schizophrenia or bipolar disorder,comprising administering a unit dose composition comprising about 180 μgof dexmedetomidine (e.g. dexmedetomidine hydrochloride) or apharmaceutically acceptable salt thereof to a human patient. Forexample, in some embodiments, the patient has schizophrenia, in someembodiments, the patient has bipolar disorder (E.g. bipolar I disorder,and in some embodiments, the patient has both schizophrenia and bipolardisorder (e.g. bipolar I disorder).

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, the composition may be administered a variety ofmeans. For example, in some embodiments, the composition comprisingdexmedetomidine (e.g. dexmedetomidine hydrochloride) or apharmaceutically acceptable salt is administered sublingually, buccally,orally, intranasally or parenterally. In some embodiments, thecomposition is administered sublingually or buccally. In someembodiments, the composition is administered sublingually in the form ofa tablet, film, spray, gel or drops. In some embodiments, thecomposition is administered buccally in the form of a film, patch ortablet.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, the method may further comprises administering asecond dose of dexmedetomidine after a period of time ranging from about30 minutes to about 12 hours. For example, the period of time may beabout 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours,or about 23 hours. In some embodiments, the second dose is administeredafter a period of about 2 hours. In some embodiments, the second doseranges from about 10 μg to about 180 μg. For example, the additionaldose may be about 10 μg, about 20 μg, about 30 μg, about 40 μg, about 50μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg,about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg,about 160 μg, about 170, or about 180 μg. In some embodiments, theadditional dose is about 60 μg or 90 μg.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, the unit dose composition may be administered to apatient in the fasted state. In some embodiments, the unit dosecomposition has been administered in the fed state.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, agitation is significantly reduced within about 2hours of administering the composition, as measured by a mean change inPositive and Negative Syndrome Scale Excited Component (PEC) scoresrelative to baseline. In some embodiments, the agitation issignificantly reduced within about 45 minutes to about 1 hour. In someembodiments, the agitation is significantly reduced in less than 45minutes (e.g. about 15 minutes, about 20 minutes, about 25 minutes,about 30 minutes). In some embodiments, the patient experiences ≥40%decrease from baseline in PEC score. For example, the patient mayexperience greater than or equal to about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, about 95%, about 100%, about 105%, about 110%, about115%, about 120%, about 125%, about 130%, about 135%, about 140%, about145%, or about 150% from baseline. Treatment efficacy may also becompared by comparing PEC score to placebo. In some embodiments, the PECscore is ≥30% lower than placebo (e.g. the placebo group has mean changefrom baseline in PEC total score of −3 and thedexmedetomidine-containing composition has a score of −3.9). Forexample, compared to placebo, the patient's PEC score may be lower bygreater than or equal to about 30,%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 100%, about 105%, about110%, about 115%, about 120%, about 125%, about 130%, about 135%, about140%, about 145%, about 150%, about 155%, about 160%, about 165%, about170%, about 175%, about 180%, about 185%, about 190%, about 195%, orabout 200%. In some embodiments, the patient experiences a mean changein PEC score of greater than about −4 (i.e. a decrease of 4 or morepoints) relative to baseline within 2 hours of administering thecomposition. For example, at the 2 hour time point, the patient mayexperience a mean change in PEC score of greater than about −4, about−5, about −6, about −7, about −8, about −9, about −10, about −11, orabout −12. In some embodiments, the decrease in PEC score (e.g. ofgreater than about −4) is maintained for at least six hours followingadministration of the composition. For example, if a patient experiencesa mean change from baseline in PEC total score of e.g. −6 at 2 hours,then at 6 hours patient's mean change in PEC score will be about −6 orlower (e.g. −7, −8, etc.). In some embodiments, the decrease in PECscore (e.g. of greater than about −4) is substantially maintained for atleast six hours following administration of the composition. Forexample, if a patient experiences a mean change from baseline in PECtotal score of e.g. −6 at 2 hours, then at 6 hours patient's mean changein PEC score will be about −4, about −5, or about −6 or lower (e.g. −7,−8, etc.). In some embodiments, the mean change in PEC score is greaterthan or equal to −8 and is maintained from 2 hours post administrationup to at least about 24 hours following administration of thecomposition.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, the subject is treated without experiencingsignificant sedation. In some embodiments, the subject is treatedwithout experiencing clinically significant cardiovascular effects.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, administration of a single dose provides a meanC_(max) within the range of about 80% to about 125% of about 100 ng/L toabout 800 ng/L. For example, the C_(max) is about 80 ng/L, about 100ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L,about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L,about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L,about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including allintegers and ranges therebetween. In some embodiments, the mean C_(max)is between about 100 ng/L to about 1000 ng/L, about 100 ng/L to about800 ng/L, about 200 ng/L to about 600 ng/L, about 300 ng/L to about 600ng/L, about 300 ng/L to about 500 ng/L, about 350 ng/L to about 500ng/L, about 300 ng/L to about 450 ng/L, about 400 ng/L to about 500ng/L, or about 400 ng/L to about 450 ng/L. In some embodiments, the meanC_(max) is within the range of about 80% to about 125% of about 440ng/L. In some embodiments, the mean C_(max) is about 440 ng/L

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, administration of a single dose provides a meanAUC_(0-inf) within the range of about 80% to about 125% of about 600hr*ng/L to about 9500 hr*ng/L. For example, the AUC_(0-inf) is about 470hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L,about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L,about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L,about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about5750 hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, toabout 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250hr*ng/L, to about 8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L,about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L,about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, to about11875 hr*ng/L, including all integers and ranges therebetween. In someembodiments, the AUC_(0-inf) is between about 500 hr*ng/L to about 10000hr*ng/L, about 1000 hr*ng/L to about 7500 hr*ng/L, about 1000 hr*ng/L toabout 6000 hr*ng/L, to about 1500 hr*ng/L to about 5000 hr*ng/L, about2000 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/L to about 4000hr*ng/L, about 2000 hr*ng/L to about 3000 hr*ng/L, about 2500 hr*ng/L toabout 4000 hr*ng/L, about 3000 hr*ng/L to about 4000 hr*ng/L, about 3500hr*ng/L to about 4000 hr*ng/L, or about 2500 hr*ng/L to about 3000hr*ng/L. In some embodiments, the mean AUC_(0-inf) is within the rangeof about 80% to about 125% of about 3800 ng*h/L. In some embodiments,the mean AUC_(0-inf) is about 3800 ng*h/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, administration of a single dose provides a meanT_(max) within the range of about 80% to about 125% of about 1 hour toabout 8 hours. For example, a single dose provides a mean T_(max) ofAbout 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h,about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h,about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about9.75 h, to about 10 h. In some embodiments, the T_(max) is between about1 h to about 8 h, about 1 h to about 6 h, about 1 h to about 4 h, about1 h to about 3 h, about 1.5 h to about 3 h, about 1.75 h to about 2.5 h,about 1.75 h to about 2.25 h. In some embodiments, the T_(max) is withinthe range of about 80% to about 125% of about 2 hours. In someembodiments, the T_(max) is about 2 hours.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, administration of a single dose provides a geometricmean C_(max) within the range of about 80% to about 125% of about 100ng/L to about 800 ng/L. For example, the C_(max) is about 80 ng/L, about100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L,about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L,about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L,about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including allintegers and ranges therebetween. In some embodiments, the geometricmean C_(max) is between about 100 ng/L to about 1000 ng/L, about 100ng/L to about 800 ng/L, about 200 ng/L to about 600 ng/L, about 300 ng/Lto about 600 ng/L, about 300 ng/L to about 500 ng/L, about 350 ng/L toabout 500 ng/L, about 300 ng/L to about 450 ng/L, about 400 ng/L toabout 500 ng/L, about 400 ng/L to about 450 ng/L, about 350 ng/L toabout 450 ng/L, or about 350 ng/L to about 400 ng/L. In someembodiments, the geometric mean C_(max) is within the range of about 80%to about 125% of about 380 ng/L. In some embodiments, the geometric meanC_(max) is about 380 ng/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, administration of a single dose provides a geometricmean AUC_(0-inf) within the range of about 80% to about 125% of about600 hr*ng/L to about 9500 hr*ng/L. For example, the AUC_(0-inf) is about470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L,about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L,about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L,about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L,about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about6500 hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L,about 8250 hr*ng/L, to about 8500 hr*ng/L, about 8750 hr*ng/L, about9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L,about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about11500 hr*ng/L, to about 11875 hr*ng/L, including all integers and rangestherebetween. In some embodiments, the AUC_(0-inf) is between about 500hr*ng/L to about 10000 hr*ng/L, about 1000 hr*ng/L to about 7500hr*ng/L, about 1000 hr*ng/L to about 6000 hr*ng/L, to about 1500 hr*ng/Lto about 5000 hr*ng/L, about 2000 hr*ng/L to about 5000 hr*ng/L, about2000 hr*ng/L to about 4000 hr*ng/L, about 2000 hr*ng/L to about 3000hr*ng/L, about 2500 hr*ng/L to about 4000 hr*ng/L, about 3000 hr*ng/L toabout 4000 hr*ng/L, about 3500 hr*ng/L to about 4000 hr*ng/L, or about2500 hr*ng/L to about 3000 hr*ng/L. In some embodiments, the geometricmean AUC_(0-inf) is within the range of about 80% to about 125% of about2880 ng*h/L. In some embodiments, the geometric mean AUC_(0-inf) isabout 2880 ng*h/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, administration of a single dose provides a geometricmean T_(max) within the range of about 80% to about 125% of about 1 hourto about 8 hours. For example, a single dose provides a geometric meanT_(max) of about 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h,about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5h, about 5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h,about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5h, about 9.75 h, to about 10 h. In some embodiments, the T_(max) isbetween about 1 h to about 8 h, about 1 h to about 6 h, about 1 h toabout 4 h, about 1 h to about 3 h, about 1.5 h to about 3 h, about 1.75h to about 2.5 h, about 1.75 h to about 2.25 h. In some embodiments, thegeometric mean T_(max) is within the range of about 80% to about 125% ofabout 2 hours. In some embodiments, the geometric mean T_(max) is about2 hours.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, administration of a single dose provides a medianC_(max) within the range of about 80% to about 125% of about 100 ng/L toabout 800 ng/L. For example, the C_(max) is about 80 ng/L, about 100ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L,about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L,about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L,about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including allintegers and ranges therebetween. In some embodiments, the medianC_(max) is between about 100 ng/L to about 1000 ng/L, about 100 ng/L toabout 800 ng/L, about 200 ng/L to about 600 ng/L, about 300 ng/L toabout 600 ng/L, about 300 ng/L to about 500 ng/L, about 350 ng/L toabout 500 ng/L, about 300 ng/L to about 450 ng/L, about 400 ng/L toabout 500 ng/L, about 400 ng/L to about 450 ng/L, about 450 ng/L toabout 500 ng/L, about 470 ng/L to about 490 ng/L. In some embodiments,the median C_(max) is within the range of about 80% to about 125% ofabout 485 ng/L. In some embodiments, the median C_(max) is about 485ng/L

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, administration of a single dose provides a medianAUC_(0-inf) within the range of about 80% to about 125% of about 600hr*ng/L to about 9500 hr*ng/L. For example, the AUC_(0-inf) is about 470hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L,about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L,about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L,about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about5750 hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, toabout 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250hr*ng/L, to about 8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L,about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L,about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, to about11875 hr*ng/L, including all integers and ranges therebetween. In someembodiments, the AUC_(0-inf) is between about 500 hr*ng/L to about 10000hr*ng/L, about 1000 hr*ng/L to about 7500 hr*ng/L, about 1000 hr*ng/L toabout 6000 hr*ng/L, to about 1500 hr*ng/L to about 5000 hr*ng/L, about2000 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/L to about 4000hr*ng/L, about 2000 hr*ng/L to about 3000 hr*ng/L, about 2500 hr*ng/L toabout 4000 hr*ng/L, about 3000 hr*ng/L to about 4000 hr*ng/L, about 3500hr*ng/L to about 4000 hr*ng/L, or about 2500 hr*ng/L to about 3000hr*ng/L. In some embodiments, the median AUC_(0-inf) is within the rangeof about 80% to about 125% of about 2900 ng*h/L. In some embodiments,the median AUC_(0-inf) is about 2900 ng*h/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, administration of a single dose provides a medianT_(max) within the range of about 80% to about 125% of about 1 hour toabout 8 hours. For example, a single dose provides a median T_(max) ofAbout 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h,about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h,about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about9.75 h, to about 10 h. In some embodiments, the T_(max) is between about1 h to about 8 h, about 1 h to about 6 h, about 1 h to about 4 h, about1 h to about 3 h, about 1.5 h to about 3 h, about 1.75 h to about 2.5 h,about 1.75 h to about 2.25 h. In some embodiments, the T_(max) is withinthe range of about 80% to about 125% of about 2 hours. In someembodiments, the T_(max) is about 2 hours.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 180 μgof dexmedetomidine, the aforementioned pharmacokinetic parameters arenon-steady state.

In some embodiments, the present disclosure provides a method oftreating agitation associated with schizophrenia or bipolar disorder,comprising administering a unit dose composition comprising about 120 toabout 180 μg of dexmedetomidine (e.g. dexmedetomidine hydrochloride) ora pharmaceutically acceptable salt thereof to a human patient. Forexample, in some embodiments, the patient has schizophrenia, in someembodiments, the patient has bipolar disorder (E.g. bipolar I disorder,and in some embodiments, the patient has both schizophrenia and bipolardisorder (e.g. bipolar I disorder).

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgto about 180 μg of dexmedetomidine, the composition may be administereda variety of means. For example, in some embodiments, the compositioncomprising dexmedetomidine (e.g. dexmedetomidine hydrochloride) or apharmaceutically acceptable salt is administered sublingually, buccally,orally, intranasally or parenterally. In some embodiments, thecomposition is administered sublingually or buccally. In someembodiments, the composition is administered sublingually in the form ofa tablet, film, spray, gel or drops. In some embodiments, thecomposition is administered buccally in the form of a film, patch ortablet.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgto about 180 μg of dexmedetomidine, the method may further comprisesadministering a second dose of dexmedetomidine after a period of timeranging from about 30 minutes to about 12 hours. For example, the periodof time may be about 30 minutes, about 1 hour, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours,about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours,about 22 hours, or about 23 hours. In some embodiments, the second doseis administered after a period of about 2 hours. In some embodiments,the second dose ranges from about 10 μg to about 180 μg. For example,the additional dose may be about 10 about 20 about 30 about 40 about 50about 60 about 70 about 80 about 90 about 100 μg, about 110 about 120about 130 about 140 about 150 about 160 about 170, or about 180 μg. Insome embodiments, the additional dose is about 60 μg or 90 μg.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgto about 180 μg of dexmedetomidine, the unit dose composition may beadministered to a patient in the fasted state. In some embodiments, theunit dose composition has been administered in the fed state.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgto about 180 μg of dexmedetomidine, agitation is significantly reducedwithin about 2 hours of administering the composition, as measured by amean change in Positive and Negative Syndrome Scale Excited Component(PEC) scores relative to baseline. In some embodiments, the agitation issignificantly reduced within about 45 minutes to about 1 hour. In someembodiments, the agitation is significantly reduced in less than 45minutes (e.g. about 15 minutes, about 20 minutes, about 25 minutes,about 30 minutes). In some embodiments, the patient experiences ≥40%decrease from baseline in PEC score. For example, the patient mayexperience greater than or equal to about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, about 95%, about 100%, about 105%, about 110%, about115%, about 120%, about 125%, about 130%, about 135%, about 140%, about145%, or about 150% from baseline. Treatment efficacy may also becompared by comparing PEC score to placebo. In some embodiments, the PECscore is ≥30% lower than placebo (e.g. the placebo group has mean changefrom baseline in PEC total score of −3 and thedexmedetomidine-containing composition has a score of −3.9). Forexample, compared to placebo, the patient's PEC score may be lower bygreater than or equal to about 30,%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 100%, about 105%, about110%, about 115%, about 120%, about 125%, about 130%, about 135%, about140%, about 145%, about 150%, about 155%, about 160%, about 165%, about170%, about 175%, about 180%, about 185%, about 190%, about 195%, orabout 200%. In some embodiments, the patient experiences a mean changein PEC score of greater than about −4 (i.e. a decrease of 4 or morepoints) relative to baseline within 2 hours of administering thecomposition. For example, at the 2 hour time point, the patient mayexperience a mean change in PEC score of greater than about −4, about−5, about −6, about −7, about −8, about −9, about −10, about −11, orabout −12. In some embodiments, the decrease in PEC score (e.g. ofgreater than about −4) is maintained for at least six hours followingadministration of the composition. For example, if a patient experiencesa mean change from baseline in PEC total score of e.g. −6 at 2 hours,then at 6 hours patient's mean change in PEC score will be about −6 orlower (e.g. −7, −8, etc.). In some embodiments, the decrease in PECscore (e.g. of greater than about −4) is substantially maintained for atleast six hours following administration of the composition. Forexample, if a patient experiences a mean change from baseline in PECtotal score of e.g. −6 at 2 hours, then at 6 hours patient's mean changein PEC score will be about −4, about −5, or about −6 or lower (e.g. −7,−8, etc.). In some embodiments, the mean change in PEC score is greaterthan or equal to −8 and is maintained from 2 hours post administrationup to at least about 24 hours following administration of thecomposition.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgto about 180 μg of dexmedetomidine, the subject is treated withoutexperiencing significant sedation. In some embodiments, the subject istreated without experiencing clinically significant cardiovasculareffects.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgto about 180 μg of dexmedetomidine, administration of a single doseprovides a mean C_(max) within the range of about 80% to about 125% ofabout 100 ng/L to about 800 ng/L. For example, the C_(max) is about 80ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L,about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L,about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L,about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L,including all integers and ranges therebetween. In some embodiments, themean C_(max) is between about 100 ng/L to about 1000 ng/L, about 100ng/L to about 800 ng/L, about 200 ng/L to about 600 ng/L, about 300 ng/Lto about 600 ng/L, about 300 ng/L to about 500 ng/L, about 350 ng/L toabout 500 ng/L, about 300 ng/L to about 450 ng/L, about 400 ng/L toabout 500 ng/L, or about 400 ng/L to about 450 ng/L, about 100 ng/L toabout 500 ng/L, about 150 ng/L to about 450 ng/L, about 150 ng/L toabout 400 ng/L, about 200 ng/L to about 350 ng/L, about 200 ng/L toabout 300 ng/L, about 200 ng/L to about 250 mg/L, or about 210 ng/L toabout 240 ng/L. In some embodiments, the mean C_(max) is within therange of about 80% to about 125% of 200 ng/L to about 500 ng/L. In someembodiments, the mean C_(max) is about 230 ng/L to about 440 ng/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgto about 180 μg of dexmedetomidine, administration of a single doseprovides a mean AUC_(0-inf) within the range of about 80% to about 125%of about 600 hr*ng/L to about 9500 hr*ng/L. For example, the AUC_(0-inf)is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L,about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L,about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about5500 hr*ng/L, about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L,about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about8000 hr*ng/L, about 8250 hr*ng/L, to about 8500 hr*ng/L, about 8750hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L,about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250hr*ng/L, about 11500 hr*ng/L, to about 11875 hr*ng/L, including allintegers and ranges therebetween. In some embodiments, the AUC_(0-inf)is between about 500 hr*ng/L to about 10000 hr*ng/L, about 1000 hr*ng/Lto about 7500 hr*ng/L, about 1000 hr*ng/L to about 6000 hr*ng/L, toabout 1500 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/L to about5000 hr*ng/L, about 2000 hr*ng/L to about 4000 hr*ng/L, about 2000hr*ng/L to about 3000 hr*ng/L, about 2500 hr*ng/L to about 4000 hr*ng/L,about 3000 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about5000 hr*ng/L, about 500 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/Lto about 3000 hr*ng/L, about 1000 hr*ng/L to about 3000 hr*ng/L, about1000 hr*ng/L to about 2500 hr*ng/L, about 1000 hr*ng/L to about 2000hr*ng/L, about 1000 hr*ng/L to about 1500 hr*ng/L, or about 1500 hr*ng/Lto about 2000 hr*ng/L, about 3500 hr*ng/L to about 4000 hr*ng/L, orabout 2500 hr*ng/L to about 3000 hr*ng/L. In some embodiments, the meanAUC_(0-inf) is within the range of about 80% to about 125% of 1400ng*h/L to about 4000 hr*ng/L. In some embodiments, the mean AUC_(0-inf)is about 3800 ng*h/L. In some embodiments, the mean AUC_(0-inf) iswithin the range of about 80% to about 125% of 1800 ng*h/L to about 3800ng*h/L.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgto about 180 μg of dexmedetomidine, administration of a single doseprovides a mean T_(max) within the range of about 80% to about 125% ofabout 1 hour to about 8 hours. For example, a single dose provides amean T_(max) of About 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h,about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h,about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about6.75 h, about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0h, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h,about 9.5 h, about 9.75 h, to about 10 h. In some embodiments, theT_(max) is between about 1 h to about 8 h, about 1 h to about 6 h, about1 h to about 4 h, about 1 h to about 3 h, about 1.5 h to about 3 h,about 1.75 h to about 2.5 h, about 1.75 h to about 2.25 h. In someembodiments, the T_(max) is within the range of about 80% to about 125%of about 2 hours. In some embodiments, the T_(max) is about 2 hours.

In accordance with some embodiments of the methods of treating agitationcomprising administering a unit dose composition comprising about 120 μgto about 180 μg of dexmedetomidine, the aforementioned pharmacokineticparameters are non-steady state.

In some embodiments, the present disclosure provides methods of treatingor ameliorating opioid withdrawal symptoms, comprising administering acomposition comprising dexmedetomidine or a pharmaceutically acceptablesalt thereof (e.g. dexmedetomidine hydrochloride) to a human patient inneed thereof, wherein the patient is at least 18 years and wherein theperiod of withdrawal is up to 14 days. “Opioid withdrawal” refers to avariety of signs and complaints appearing with the abrupt removal of, ora rapid decrease in the regular dosage of opioids. Physicalmanifestations may include sweating, nausea, yawning, chills, diarrhea,papillary dilation, piloerection, tachycardia, increased blood pressure,hypersensitivity to pain, stomach cramps, and muscle cramps.Psychological manifestations of opioid withdrawal observed may includeagitation, dysphoria, restlessness, irritability, anxiety, anddepression. In some embodiments, the opioid withdrawal symptom isagitation. Onset often begins within 6-24 hours from last opioid use. Insome embodiments, treating or ameliorating opioid withdrawal refers tothe treatment or lessening of one or more of the aforementionedsymptoms. The treating or ameliorating may be measured by a variety ofwell-known means in the art, including but not limited to, the ClinicalOpiate Withdrawal Scale (COWS) and/or Short Opiate Withdrawal Scale ofGossop (SOWS-Gossop) score.

Thus, in some embodiments, the present disclosure provides methods oftreating or ameliorating agitation associated with opioid withdrawalsymptoms. In some embodiments, the treatment or amelioration comprisesreducing the period of opioid withdrawal. For example, a patient treatedin accordance with the embodiments of the present disclosure, mayexperience an opioid withdrawal period of about 3, about 4, about 5,about 6, about 7, about 8, about 9, about 10, about 11, about 12, about13, or about 14 days, where a similar patient that was not treated inaccordance with the embodiments of the present disclosure will have alonger opioid withdrawal treatment.

In some embodiments, the composition is administered twice daily. Insome embodiments, the composition comprises a dose range ofdexmedetomidine or a pharmaceutically acceptable salt thereof of betweenabout 30 μg and about 200 μg. For example, the composition comprises aunit dose of about 30 μg, about 60 μg, about 90 μg, about 120 μg, or 180μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. Insome embodiments, a single dose of a composition comprising about 180 μgdexmedetomidine or a pharmaceutically acceptable salt thereof iseffective for up to at least about 24 hours. In some embodiments, thecomposition is administered twice daily for 7 days.

In some embodiments, the patient is suffering from opioid withdrawal,wherein the opioid is one or more of fentanyl, morphine, codeine,heroin, oxycodone, hydrocodone, alfentanil carfentanil, tramadol,hydromorphone, buprenorphine, naloxone, naltrexone, remifentanilbutorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene)thebaine, sufentanil and pentazocine. In some embodiments, the opioid isfentanyl. In some embodiments, the opioid had been administered foramount of time longer than neonate treatment prior to withdrawal.

In some embodiments, the composition is administered sublingually,buccally, orally, intranasally or parenterally. In some embodiments, thecomposition is administered sublingually in the form of a tablet, film,spray, gel or drops. In some embodiments, the composition isadministered sublingually in the form of a film. In some embodiments,the composition is administered buccally in the form of a film, patch ortablet. In some embodiments, the composition is administered buccally inthe form of a film. In some embodiments, the patient is treated withoutalso inducing clinically significant cardiovascular effects.

In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising from about 20 μg to about 240 μg dexmedetomidineor a pharmaceutically acceptable salt thereof (e.g. dexmedetomidinehydrochloride). In some embodiments, the dose of dexmedetomidine isabout 120 μg. In some embodiments, the dose of dexmedetomidine is about180 μg.

In some embodiments, the composition is formulated for sublingual orbuccal administration. In some embodiments, the composition isformulated for sublingual administration in the form of a tablet, film,spray, gel or drops. In some embodiments, the composition is formulatedfor buccal administration in the form of a film, patch or tablet.

In some embodiments, the pharmaceutical composition comprising fromabout 20 μg to about 240 μg dexmedetomidine is administered to a patienthaving agitation associated with schizophrenia or bipolar disorder, theagitation is significantly reduced within about 2 hours of administeringthe composition as measured by a mean change in Positive and NegativeSyndrome Scale Excited Component (PEC) scores relative to baseline. Forexample, the agitation is significantly reduced with 30 minutes, 45minutes, 1 hour, 90 minutes, or about 2 hours. In some embodiments, thepatient experiences ≥40% decrease from baseline in PEC score. Forexample, the patient may experience greater than or equal to about 40%,about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%,about 110%, about 115%, about 120%, about 125%, about 130%, about 135%,about 140%, about 145%, or about 150% from baseline. Treatment efficacymay also be compared by comparing PEC score to placebo. In someembodiments, the PEC score is ≥30% lower than placebo (e.g. the placebogroup has mean change from baseline in PEC total score of −3 and thedexmedetomidine-containing composition has a score of −3.9). Forexample, compared to placebo, the patient's PEC score may be lower bygreater than or equal to about 30,%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 100%, about 105%, about110%, about 115%, about 120%, about 125%, about 130%, about 135%, about140%, about 145%, about 150%, about 155%, about 160%, about 165%, about170%, about 175%, about 180%, about 185%, about 190%, about 195%, orabout 200%. In some embodiments, the patient experiences a mean changein PEC score of greater than about −4 (i.e. a decrease of 4 or morepoints) relative to baseline within 2 hours of administering thecomposition. For example, at the 2 hour time point, the patient mayexperience a mean change in PEC score of greater than about −4, about−5, about −6, about −7, about −8, about −9, about −10, about −11, orabout −12. In some embodiments, the decrease in PEC score (e.g. ofgreater than about −4) is maintained for at least six hours followingadministration of the composition. For example, if a patient experiencesa mean change from baseline in PEC total score of e.g. −6 at 2 hours,then at 6 hours patient's mean change in PEC score will be about −6 orlower (e.g. −7, −8, etc.). In some embodiments, the mean change in PECscore is greater than or equal to −8 and is maintained from 2 hours postadministration up to at least about 24 hours following administration ofthe composition.

In accordance with some embodiments of the pharmaceutical compositioncomprising from about 20 μg to about 240 μg dexmedetomidine, the subjectis treated without experiencing significant sedation. In someembodiments, the subject is treated without experiencing clinicallysignificant cardiovascular effects.

Administration of a single dose of the pharmaceutical compositioncomprising from about 20 μg to about 240 μg dexmedetomidine provides amean C_(max) within the range of about 80% to about 125% of about 100ng/L to about 800 ng/L. For example, the C_(max) is about 80 ng/L, about100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L,about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L,about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L,about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including allintegers and ranges therebetween. In some embodiments, the mean C_(max)is between about 100 ng/L to about 1000 ng/L, about 100 ng/L to about800 ng/L, about 200 ng/L to about 600 ng/L, about 300 ng/L to about 600ng/L, about 300 ng/L to about 500 ng/L, about 350 ng/L to about 500ng/L, about 300 ng/L to about 450 ng/L, about 400 ng/L to about 500ng/L, or about 400 ng/L to about 450 ng/L, about 100 ng/L to about 500ng/L, about 150 ng/L to about 450 ng/L, about 150 ng/L to about 400ng/L, about 200 ng/L to about 350 ng/L, about 200 ng/L to about 300ng/L, about 200 ng/L to about 250 mg/L, or about 210 ng/L to about 240ng/L. In some embodiments, the mean C_(max) is within the range of about80% to about 125% of 200 ng/L to about 500 ng/L. In some embodiments,the mean C_(max) is about 230 ng/L to about 440 ng/L.

Administration of a single dose of the pharmaceutical compositioncomprising from about 20 μg to about 240 μg dexmedetomidine provides amean AUC_(0-inf) within the range of about 80% to about 125% of about600 hr*ng/L to about 9500 hr*ng/L. For example, the AUC_(0-inf) is about470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L,about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L,about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L,about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L,about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about6500 hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L,about 8250 hr*ng/L, to about 8500 hr*ng/L, about 8750 hr*ng/L, about9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L,about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about11500 hr*ng/L, to about 11875 hr*ng/L, including all integers and rangestherebetween. In some embodiments, the AUC_(0-inf) is between about 500hr*ng/L to about 10000 hr*ng/L, about 1000 hr*ng/L to about 7500hr*ng/L, about 1000 hr*ng/L to about 6000 hr*ng/L, to about 1500 hr*ng/Lto about 5000 hr*ng/L, about 2000 hr*ng/L to about 5000 hr*ng/L, about2000 hr*ng/L to about 4000 hr*ng/L, about 2000 hr*ng/L to about 3000hr*ng/L, about 2500 hr*ng/L to about 4000 hr*ng/L, about 3000 hr*ng/L toabout 4000 hr*ng/L, about 500 hr*ng/L to about 5000 hr*ng/L, about 500hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about 3000 hr*ng/L,about 1000 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L to about2500 hr*ng/L, about 1000 hr*ng/L to about 2000 hr*ng/L, about 1000hr*ng/L to about 1500 hr*ng/L, or about 1500 hr*ng/L to about 2000hr*ng/L, about 3500 hr*ng/L to about 4000 hr*ng/L, or about 2500 hr*ng/Lto about 3000 hr*ng/L. In some embodiments, the mean AUC_(0-inf) iswithin the range of about 80% to about 125% of 1400 ng*h/L to about 4000hr*ng/L. In some embodiments, the mean AUC_(0-inf) is about 3800 ng*h/L.In some embodiments, the mean AUC_(0-inf) is within the range of about80% to about 125% of 1800 ng*h/L to about 3800 ng*h/L.

Administration of a single dose of the pharmaceutical compositioncomprising from about 20 μg to about 240 μg dexmedetomidine provides amean T_(max) within the range of about 80% to about 125% of about 1 hourto about 8 hours. For example, a single dose provides a mean T_(max) ofAbout 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h,about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h,about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about9.75 h, to about 10 h. In some embodiments, the T_(max) is between about1 h to about 8 h, about 1 h to about 6 h, about 1 h to about 4 h, about1 h to about 3 h, about 1.5 h to about 3 h, about 1.75 h to about 2.5 h,about 1.75 h to about 2.25 h. In some embodiments, the T_(max) is withinthe range of about 80% to about 125% of about 2 hours. In someembodiments, the T_(max) is about 2 hours.

In some embodiments, the aforementioned pharmacokinetic parameters arenon-steady state.

In some embodiments, the present disclosure provides methods of reducingagitation to a 1 (very much improved) or 2 (much improved) within 2hours of administering a composition comprising dexmedetomidine or apharmaceutically acceptable salt thereof (e.g. dexmedetomidinehydrochloride), as measured by the Clinical GlobalImpression—Improvement Scale. In some embodiments, the agitation isreduced within about 30 minutes to about 1 hour. In some embodiments,the reduction in agitation is maintained for greater than about 2 hours.For example, the reduction in agitation is maintained for about 2 hours,about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours,about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours,about 21 hours, about 22 hours, about 23, or about 24 hours. In someembodiments, the composition comprises about 120 μg of dexmedetomidine.In some embodiments, the composition comprises about 180 μg ofdexmedetomidine. In some embodiments, the patient has schizophrenia. Insome embodiments, the patient has bipolar disorder.

In some embodiments, the present disclosure provides methods of reducingagitation to a 3 (mild agitation) or 4 (normal behavior) within 2 hoursof administering a composition comprising dexmedetomidine or apharmaceutically acceptable salt thereof, as measured by theAgitation-Calmness Evaluation Scale (ACES). In some embodiments, theagitation is reduced within about 30 minutes to about 1 hour. In someembodiments, the reduction in agitation is reduced to a 4 (normalbehavior). In some embodiments, the reduction in agitation is maintainedfor greater than about 2 hours. For example, the reduction in agitationis maintained for about 2 hours, about 3 hours, about 4 hours, about 5hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about10 hours, about 11 hours, about 12 hours, about 13 hours, about 14hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours,about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23hours, or about 24 hours. In some embodiments, the composition comprisesabout 120 μg of dexmedetomidine. In some embodiments, the compositioncomprises about 180 μg of dexmedetomidine. In some embodiments, thepatient has schizophrenia. In some embodiments, the patient has bipolardisorder.

In some embodiments, the present disclosure provides methods ofachieving a ≥40% reduction in agitation, within 2 hours of administeringa composition comprising dexmedetomidine or a pharmaceuticallyacceptable salt thereof, as measured by the PEC scale. In someembodiments, the agitation is reduced within about 30 minutes to about 1hour. In some embodiments, the reduction in agitation ≥40%, ≥50%, ≥60%,≥70%, ≥80%, ≥90%, or ≥100%. In some embodiments, the reduction inagitation is maintained for greater than about 2 hours. For example, thereduction in agitation is maintained for about 2 hours, about 3 hours,about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours,about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours,about 22 hours, about 23 hours, or about 24 hours. In some embodiments,the composition comprises about 120 μg of dexmedetomidine. In someembodiments, the composition comprises about 180 μg of dexmedetomidine.In some embodiments, the patient has schizophrenia. In some embodiments,the patient has bipolar disorder.

In some embodiments, the present disclosure provides a method ofachieving a PEC score reduction in agitation for a sustained period oftime in a subject with bipolar or schizophrenic subject comprisingadministering to the subject a pharmaceutical composition comprisingdexmedetomidine or a pharmaceutically acceptable salt thereof at a doseof about 120 μg to about 180 μg wherein the PEC score reduction is about−8 to about −10 and wherein the sustained period is about 2 hours toabout 6 hours. In some embodiments, the composition comprisesdexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof is administered at a dose ofabout 120 μg. In some embodiments, dexmedetomidine or a pharmaceuticallyacceptable salt thereof is administered at a dose of about 180 μg. Insome embodiments, the sustained period is about 2 hours, about 3 hours,about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours,about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours,about 22 hours, about 23 hours, or about 24 hours. In some embodiments,the PEC score reduction is about −8, about −9, or about −10.

In some embodiments, the present disclosure provides a method ofachieving an ACES score improvement for a sustained period of time in asubject with bipolar or schizophrenic subject comprising administeringto the subject a pharmaceutical composition comprising dexmedetomidineor a pharmaceutically acceptable salt thereof at a dose of about 120 μgto about 180 μg wherein the ACES score is improved to about 3 to about 4and wherein the sustained period is about 2 hours to about 6 hours. Insome embodiments, the composition comprises dexmedetomidinehydrochloride. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof is administered at a dose ofabout 120 mcg. In some embodiments, dexmedetomidine or apharmaceutically acceptable salt thereof is administered at a dose ofabout 180 mcg. In some embodiments, the sustained period is about 2hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours,about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours,about 21 hours, about 22 hours, about 23 hours, or about 24 hours. Insome embodiments, the ACES score is about 4.

In some embodiments, the present disclosure provides a method ofachieving an CGI-I score improvement for a sustained period of time in asubject with bipolar or schizophrenic subject comprising administeringto the subject a pharmaceutical composition comprising dexmedetomidineor a pharmaceutically acceptable salt thereof at a dose of about 120 μgto about 180 μg wherein the CGI-I score is improved to about a 1 (verymuch improved) or about a 2 (much improved) and wherein the sustainedperiod is about 2 hours to about 6 hours. In some embodiments, thecomposition comprises dexmedetomidine hydrochloride. In someembodiments, dexmedetomidine or a pharmaceutically acceptable saltthereof is administered at a dose of about 120 μg. In some embodiments,dexmedetomidine or a pharmaceutically acceptable salt thereof isadministered at a dose of about 180 μg. In some embodiments, thesustained period is about 2 hours, about 3 hours, about 4 hours, about 5hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about10 hours, about 11 hours, about 12 hours, about 13 hours, about 14hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours,about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23hours, or about 24 hours. In some embodiments, the CGI-I score is about1.

SPECIFIC EMBODIMENTS

Embodiment 1. A method of treating agitation or signs of agitation in ahuman subject with schizophrenia or bipolar disorder, without alsoinducing significant sedation, comprising administering dexmedetomidineor a pharmaceutically acceptable salt thereof at a dose resulting in amean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞, of about 3800 ng*h/L.

Embodiment 2. A method of treating agitation or signs of agitation in ahuman subject with schizophrenia or bipolar disorder, without alsoinducing significant sedation, comprising administering dexmedetomidineor a pharmaceutically acceptable salt thereof at a dose resulting in atotal exposure of dexmedetomidine, as measured by plasma AUC from T0 toT∞, from about 600 to about 12600 ng*h/L.

Embodiment 3. A methods of treating agitation or signs of agitation in ahuman subject with schizophrenia or bipolar disorder, without alsoinducing significant sedation, comprising administering dexmedetomidineor a pharmaceutically acceptable salt thereof at a dose resulting in amean total exposure of dexmedetomidine, as measured by plasma AUC fromT0 to T∞, of about 1800 ng*h/L.

Embodiment 4. A method of treating agitation or signs of agitation in ahuman subject with schizophrenia or bipolar disorder, without alsoinducing significant sedation, comprising administering dexmedetomidineor a pharmaceutically acceptable salt thereof at a dose resulting in atotal exposure of dexmedetomidine, as measured by plasma AUC from T0 toT∞, from about 590 ng*h/L to about 8750 ng*h/L.

Embodiment 5. The method of embodiments 1 to 4, wherein said agitationor signs of agitation is associated with schizophrenia.

Embodiment 6 The method of embodiments 1 to 4, wherein dexmedetomidineor a pharmaceutically acceptable salt thereof is administeredsublingually, buccally, orally, intranasally or parenterally.

Embodiment 7. The method of embodiment 6, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered sublingually orbuccally.

Embodiment 8. The method of embodiment 6, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered sublingually.

Embodiment 9. The method of embodiment 6, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered sublingually inthe form of a tablet, film, spray, gel or drops.

Embodiment 10. The method of embodiment 6, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered sublingually inthe form of a film.

Embodiment 11. The method of embodiment 6, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered buccally.

Embodiment 12. The method of embodiment 6, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered buccally in theform of a film, patch or tablet.

Embodiment 13. The method of embodiment 6, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered parenterally.

Embodiment 14. The method of embodiment 13, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered parenterally inthe form of an intramuscular injection.

Embodiment 15. The method of embodiment 6, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered orally.

Embodiment 16. The method of any one of embodiments 1 to 15, whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered as a single dose.

Embodiment 17. The method of any one of embodiments 1 to 15, whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered as a single dose containing about 180 μg dexmedetomidine ora pharmaceutically acceptable salt thereof.

Embodiment 18. The method of any one of embodiments 1 to 15, whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered as a single dose containing about 120 μg dexmedetomidine ora pharmaceutically acceptable salt thereof.

Embodiment 19. The method of embodiment 14, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered at a dose ofabout 140 to 190 μg.

Embodiment 20 The method of embodiment 15, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered at a dose ofabout 900 to 1200 μg.

Embodiment 21. The method of any one of embodiments 1 to 20, whereinagitation or signs of agitation is treated without also inducingclinically significant cardiovascular effects.

Embodiment 22. The method of any one of embodiments 1 to 21, whereinagitation or signs of agitation are significantly reduced within 60minutes of administering dexmedetomidine or a pharmaceuticallyacceptable salt thereof.

Embodiment 23. The method of any one of embodiments 1 to 21, whereinagitation or signs of agitation are significantly reduced within 60minutes of administering dexmedetomidine or a pharmaceuticallyacceptable salt thereof, as measured by a significant relative change inPEC scores just prior to and 60 minutes after administeringdexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 24. The method of embodiment 23, wherein the said relativePEC scores are different by at least six points.

Embodiment 25. The method of embodiment 23, wherein the said relativePEC scores are different by at least eight points.

Embodiment 26. The method of embodiment 24 or 25, wherein the differencein relative PEC scores is maintained for at least six hours followingadministration of dexmedetomidine or a pharmaceutically acceptable saltthereof.

Embodiment 27. The method of embodiment 23, wherein the said relativePEC scores are different by at least eight points, and wherein thisdifference of at least eight points is maintained for up to at leastabout 24 hours following administration of dexmedetomidine or apharmaceutically acceptable salt thereof.

Embodiment 28. The method of any one of embodiments 1 to 27, wherein themean plasma Cmax is about 400 ng/L.

Embodiment 29. The method of any one of embodiments 1 to 28, wherein themedian plasma Tmax is about 2.0 hours.

Embodiment 30. The method of any one of embodiments 1 to 29, wherein themean plasma Cmax is about 400 ng/L and the median plasma Tmax is about2.0 hours.

Embodiment 31. The method of any one of embodiments 28 to 30, whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered sublingually.

Embodiment 32. The method of any one of embodiments 28 to 30, whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered sublingually in the form of a film.

Embodiment 33. The method of any one of embodiments 1 to 27, wherein theplasma Cmax is about 100 to about 1100 ng/L.

Embodiment 34. The method of any one of embodiments 1 to 27, wherein theplasma Cmax is about 200 to about 800 ng/L.

Embodiment 35. The method of any one of embodiments 1 to 27, wherein theplasma Cmax is about 3000 to about 5000 ng/L.

Embodiment 36. The method of any one of embodiments 33 to 35, whereinthe plasma Tmax is about 1 to about 8 hours.

Embodiment 37. The method of any one of embodiments 33 to 35, whereinthe plasma Tmax is about 5 minutes to about 4 hours.

Embodiment 38. The method of any one of embodiments 33 to 35, whereinthe plasma Tmax is about 5 to about 15 minutes.

Embodiment 39. A method of treating a condition (e.g. agitation) in ahuman subject, comprising administering to said subject about 180 μg ofdexmedetomidine or a pharmaceutically acceptable salt thereofsublingually or buccally to said subject, resulting in mean plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values: Cmax of from about 300 ng/L to about 500. ng/L (e.g.about 400 ng/L) and AUC from T0 to T∞ of from about 2300 ng*h/L to about3600 ng*h/L (e.g. about 2900 ng*h/L).

Embodiment 40. A method of treating a condition (e.g. agitation) in ahuman subject, comprising administering to said subject about 180 μg ofdexmedetomidine or a pharmaceutically acceptable salt thereofsublingually or buccally to said subject, resulting in plasma absorptionlevels of dexmedetomidine from about 80% to about 125% of the followingvalues: Cmax from about 100 ng/L to about 800 ng/L and AUC from T0 to T∞of about 600 hr*ng/L to about 9500 hr*ng/L.

Embodiment 41. A method of treating a condition (e.g. agitation) in ahuman subject, comprising administering to said subject about 120 μg ofdexmedetomidine or a pharmaceutically acceptable salt thereofsublingually or buccally to said subject, resulting in mean plasmaabsorption levels of dexmedetomidine from about 80% to about 125% of thefollowing values Cmax from about 150 ng/L to about 300 ng/L (e.g. about220 ng/L) and AUC from T0 to T∞ of from about 1100 ng*h/L to about 1800ng*h/L (e.g. about 1420 ng*h/L).

Embodiment 42. A method of treating a condition (e.g. agitation) in ahuman subject, comprising administering to said subject about 120 μg ofdexmedetomidine or a pharmaceutically acceptable salt thereofsublingually or buccally to said subject, resulting in plasma absorptionlevels of dexmedetomidine from about 80% to about 125% of the followingvalues: Cmax from about 110 ng/L to about 400 ng/L and AUC from T0 to T∞of about 590 hr*ng/L to about 4400 hr*ng/L.

Embodiment 43. The method of embodiments 39 to 42, wherein the conditionis agitation or signs of agitation.

Embodiment 44. The method of embodiment 39 to 43, wherein said agitationor signs of agitation is associated with schizophrenia or bipolardisorder.

Embodiment 45. The method of any one of embodiments 39 to 44 whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered oromucosally (e.g. sublingually or buccally).

Embodiment 46. The method of embodiments 45, wherein dexmedetomidine ora pharmaceutically acceptable salt thereof is administered sublinguallyin the form of a tablet, film, spray, gel or drops.

Embodiment 47. The method of embodiment 46, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered in the form ofa film.

Embodiment 48. The method of embodiment 45, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered buccally.

Embodiment 49. The method of embodiment 48, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered buccally in theform of a film, patch or tablet.

Embodiment 50. The method of embodiment 49, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered in the form ofa film.

Embodiment 51. The method of any one of embodiments 39 to 50, whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered as a single dose.

Embodiment 52. The method of any one of embodiments 39 to 51, whereinthe subject is treated without also inducing significant sedation.

Embodiment 53. The method of any one of embodiments 39 to 52, whereinthe subject is treated without also inducing clinically significantcardiovascular effects.

Embodiment 54. The method of any one of embodiments 43 to 53, whereinagitation or signs of agitation are significantly reduced within 60minutes of administering dexmedetomidine or a pharmaceuticallyacceptable salt thereof.

Embodiment 55. The method of any one of embodiments 43 to 54, whereinagitation or signs of agitation are significantly reduced within 60minutes of administering dexmedetomidine or a pharmaceuticallyacceptable salt thereof, as measured by the relative PEC scores justprior to and 60 minutes after administering dexmedetomidine or apharmaceutically acceptable salt thereof.

Embodiment 56. The method of embodiment 55, wherein the said relativePEC scores are different by at least six points.

Embodiment 57. The method of embodiment 55, wherein the said relativePEC scores are different by at least eight points.

Embodiment 58. The method of embodiment 56 or 57 wherein the differencein relative PEC scores is maintained for at least six hours followingadministration of dexmedetomidine or a pharmaceutically acceptable saltthereof.

Embodiment 59. The method of embodiment 55, wherein the said relativePEC scores are different by at least eight points, and wherein thisdifference of at least eight points is maintained for up to at leastabout 24 hours following administration of dexmedetomidine or apharmaceutically acceptable salt thereof.

Embodiment 60. The method of any one of embodiments 39 to 59, whereinthe median plasma Tmax is about 2 hours.

Embodiment 61. The method of any one of embodiments 39 to 59, whereinthe plasma Tmax is about 1 to about 8 hours.

Embodiment 62. A method of treating agitation or signs of agitation in ahuman subject with schizophrenia or bipolar disorder, without alsoinducing significant sedation, comprising administering 180 μgdexmedetomidine or a pharmaceutically acceptable salt thereof as asingle dose.

Embodiment 63. A method of treating agitation or signs of agitation in ahuman subject with schizophrenia or bipolar disorder, without alsoinducing significant sedation, comprising administering 120 μgdexmedetomidine or a pharmaceutically acceptable salt thereof as asingle dose.

Embodiment 64. A method of mitigation or preventing the occurrence of afurther agitation event in a human subject with schizophrenia or bipolardisorder within about 24 hours of an earlier agitation event, comprisingadministering about 180 μg dexmedetomidine or a pharmaceuticallyacceptable salt thereof as a single dose immediately following saidearlier agitation event.

Embodiment 65. A method of mitigation or preventing the occurrence of afurther agitation event in a human subject with schizophrenia or bipolardisorder within about 24 hours of an earlier agitation event, comprisingadministering about 120 μg dexmedetomidine or a pharmaceuticallyacceptable salt thereof as a single dose immediately following saidearlier agitation event.

Embodiment 66. The method of embodiment 62 or 63, wherein said agitationor signs of agitation is associated with schizophrenia.

Embodiment 67. A method of treating agitation or signs of agitation in ahuman subject with dementia, without also inducing significant sedation,comprising oromucosally administering about 30 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof one to six times a day at adosing interval of at least 2 hours.

Embodiment 68. A method of treating agitation or signs of agitation in ahuman subject with dementia, without also inducing significant sedation,comprising oromucosally administering about 60 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof one to six times a day at adosing interval of at least 2 hours.

Embodiment 69. A method of treating agitation or signs of agitation in ahuman subject with dementia, without also inducing significant sedation,comprising oromucosally administering about 90 μg of dexmedetomidine ora pharmaceutically acceptable salt thereof one to four times a day at adosing interval of at least 2 hours.

Embodiment 70. A method of treating agitation or signs of agitation in ahuman subject with delirium hospitalized in ICU, without also inducingsignificant sedation, comprising oromucosally administering about 20 μgof dexmedetomidine or a pharmaceutically acceptable salt one to fourtimes within 6 hours of first dose at a dosing interval of at least 30minutes thereof.

Embodiment 71. A method of treating agitation or signs of agitation in ahuman subject with delirium hospitalized in ICU, without also inducingsignificant sedation, comprising oromucosally administering about 60 μgof dexmedetomidine or a pharmaceutically acceptable salt thereof one tofour times within 6 hours of first dose at a dosing interval of at least30 minutes

Embodiment 72. A method of reducing a period of opioid withdrawal byadministering to a human subject of at least 18 years in need thereofdexmedetomidine twice daily for the period of withdrawal, wherein theperiod of withdrawal is up to 14 days.

Embodiment 73. The method of embodiment 72, wherein the dexmedetomidineis administered at a dose range between 30 μg to about 200 μg.

Embodiment 74. The method of embodiment 73, wherein the dexmedetomidineis administered at a unit dose of about 30 μg, 60 μg, 90 μg, 120 μg and180 μg. Embodiment 75. The method of embodiment 72, wherein the periodof withdrawal is up to: 13 days, 12 days, 11 days, 10 days, 9 days, 8days, 7 days, 6 days, 5 days, 4 days, or 3 days.

Embodiment 76. The method of embodiment 72, wherein the opioid isselected from the group comprising of fentanyl, morphine, codeine,heroin, oxycodone, hydrocodone, alfentanil carfentanil, tramadol,hydromorphone, buprenorphine, naloxone, naltrexone, remifentanilbutorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene)thebaine, sufentanil or pentazocine.

Embodiment 77. The method of embodiment 72, wherein the opioid had beenadministered for amount of time longer than neonate treatment prior towithdrawal.

Embodiment 78. A method of treating agitation or signs of agitation in ahuman subject with schizophrenia or bipolar disorder, without alsoinducing significant sedation, comprising administering an oromucosalfilm comprising about 120 μg or about 180 μg dexmedetomidine or apharmaceutically acceptable salt thereof as a single dose.

Embodiment 79. The method of embodiment 78, wherein the subject has beenpreviously administered a liquid formulation of dexmedetomidine or apharmaceutically acceptable salt thereof via a parenteral route(intravenous, intramuscular, subcutaneous injection or intravenousinfusion).

Embodiment 80. The method of any of embodiments 78 and 79, wherein theoromucosal administration is followed within 3 to 5 hours of previousadministration of liquid formulation of dexmedetomidine via a parenteralroute.

Embodiment 81. The method of embodiment 78, wherein the parenteraladministration is followed within 3 to 5 hours of previousadministration of oromucosal film.

Embodiment 82. The method of embodiment 79, wherein the liquidformulation is prefilled in disposable syringes for self-administrationby patients with an auto-injector.

Embodiment 83. The method of embodiment 78, wherein the subject iscurrently is co-treated with an anti-psychotic.

Embodiment 84. The method of embodiments 83, wherein the anti-psychoticis selected from but are not limited to aripiprazole, benperidol.flupentixol, amisulpride, chlorpromazine, asenapine, risperidone,ziprasidone, lurasidone, clozapine, cariprazine, olanzapine andquetiapine. In a preferred embodiment, the anti-psychotic isaripiprazole.

Embodiments 85. The method of embodiment 72, wherein improvement in thesubject is assessed using a Clinical Opiate Withdrawal Scale and/or theShort Opiate Withdrawal Scale of Gossop (e.g. over a 10-day period)after following the treatment.

Embodiment 86. The method of embodiment 70 or 71, wherein changes inseverity of delirium are measured using DRS-R-98 scale.

Embodiment 87. The method of embodiment 70 or 71, wherein changes inagitation are monitored using RASS scale.

Embodiment 88. The method of any one of the embodiments 62, 63, 64, 65,wherein dexmedetomidine or a pharmaceutically acceptable salt thereof isadministered oromucosally (e.g. sublingually, buccally), orally,intranasally or parenterally.

Embodiment 89. The method of any one of the embodiments 67, 68, 69, 70,71 and 72, wherein dexmedetomidine or a pharmaceutically acceptable saltthereof is administered oromucosally (e.g. sublingually or buccally) inthe form of a tablet, film, spray, gel or drops.

Embodiment 90. The method of embodiment 89, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered sublingually inthe form of a tablet, film, spray, gel or drops.

Embodiment 91. The method of embodiment 90, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered sublingually inthe form of a film.

Embodiment 92. The method of embodiment 89, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered buccally in theform of a film, patch or tablet.

Embodiment 93. The method of embodiment 92, wherein dexmedetomidine or apharmaceutically acceptable salt thereof is administered buccally in theform of a film.

Embodiment 94. The method of embodiments 62 to 65, whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered parenterally in the form of an intravenous or intramuscularinjection or an intravenous infusion.

Embodiment 95. The method of embodiments 62 to 65, whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered by intramuscular injection.

Embodiment 96. The method of embodiments 62 to 65, whereindexmedetomidine or a pharmaceutically acceptable salt thereof isadministered once a day.

Embodiment 97. The method of claims 62 to 65, 67, 68, 69, 70, 71 and 72,wherein agitation or signs of agitation is treated without also inducingclinically significant cardiovascular effects.

Embodiment 98. The method of claim 62 or claim 64, wherein a single doseof about 180 μg dexmedetomidine or a pharmaceutically acceptable saltthereof is effective for up to at least about 24 hours.

Embodiment 99. The method of embodiments 62 to 65, wherein agitation orsigns of agitation are significantly reduced within 60 minutes ofadministering dexmedetomidine or a pharmaceutically acceptable saltthereof, as measured by a significant relative change in PEC scores justprior to and 60 minutes after administering dexmedetomidine or apharmaceutically acceptable salt thereof.

Embodiment 100. The method of embodiment 99, wherein the said relativePEC scores are different by at least six points or eight points.

Embodiment 101. The method of embodiment 99 or embodiment 100, whereinthe difference in relative PEC scores is maintained for at least sixhours following administration of dexmedetomidine or a pharmaceuticallyacceptable salt thereof.

Embodiment 102. The method of embodiment 99 or embodiment 100, whereinthe said relative PEC scores are different by at least eight points, andwherein this difference of at least eight points is maintained for up toat least about 24 hours following administration of dexmedetomidine or apharmaceutically acceptable salt thereof.

Embodiment 103. The method of any of relevant preceding embodiments,where dexmedetomidine or a pharmaceutically acceptable salt thereof isadministered as a film, wherein said film is a self-supporting,dissolvable, film, comprising:

-   -   (i) dexmedetomidine or a pharmaceutically acceptable salt        thereof;    -   (ii) one or more water-soluble polymers; and, optionally,    -   (iii) one or more pharmaceutically acceptable carriers.

Embodiment 104. The method of embodiment 103, wherein (ii) comprises alow molecular weight, water-soluble polymer and two high molecularweight, water-soluble polymers.

Embodiment 105. The method of embodiment 104, wherein the low molecularweight, water-soluble polymer has a molecular weight from about 5,000daltons to about 49,000 daltons, and each high molecular weight,water-soluble polymer has a molecular weight of greater than about60,000 daltons.

Embodiment 106. The method of embodiment 104, wherein the low molecularweight, water-soluble polymer has a molecular weight of about 40,000daltons, one of the two high molecular weight, water-soluble polymershas a molecular weight of about 140,000 daltons, and the other highmolecular weight, water-soluble polymer has a molecular weight of about370,000 daltons.

Embodiment 107. The method of any one of embodiments 103 to 106, whereineach water-soluble polymer is hydroxypropyl cellulose.

Embodiment 108. The method of any one of embodiments 103 to 106, whereinthe film also comprises a polyethylene oxide.

Embodiment 109. The method of embodiment 108, wherein the polyethyleneoxide has a molecular weight of about 600,000 daltons.

Embodiment 110. The method of any of relevant preceding embodiments,where dexmedetomidine or a pharmaceutically acceptable salt thereof isadministered as a film, wherein said film is a self-supporting,dissolvable, film, comprising:

-   -   (i) dexmedetomidine or a pharmaceutically acceptable salt        thereof;    -   (ii) a low molecular weight, water-soluble polymer having a        molecular weight of about 40,000 daltons;    -   (iii) a high molecular weight, water-soluble polymer having a        molecular weight from about 140,000 daltons;    -   (iv) a high molecular weight, water-soluble polymer having a        molecular weight from about 370,000 daltons; and    -   (v) a water-soluble polyethylene oxide having a molecular weight        of about 600,000 daltons.

Embodiment 111. The method of embodiment 110, wherein the filmcomponents excluding dexmedetomidine or a pharmaceutically acceptablesalt thereof form a single layer film substrate, and dexmedetomidine ora pharmaceutically acceptable salt thereof is present on the surface ofthe film substrate.

Embodiment 112. The method of embodiment 111, wherein dexmedetomidine ora pharmaceutically acceptable salt thereof is present on the surface ofthe film substrate within a composition comprising dexmedetomidine or apharmaceutically acceptable salt thereof, a low molecular weight,water-soluble polymer having a molecular weight of about 40,000 daltons,and a high molecular weight, water-soluble polymer having a molecularweight of about 140,000 daltons.

Embodiment 113. A method of treating agitation associated withschizophrenia or bipolar disorder, comprising administering a unit dosecomposition comprising about 120 μg of dexmedetomidine or apharmaceutically acceptable salt thereof to a human patient.

Embodiment 114. The method of embodiment 113, wherein the patient hasschizophrenia.

Embodiment 115. The method of embodiment 113 or embodiment 114, whereinthe patient has bipolar I disorder.

Embodiment 116. The method of any one of embodiments 113-115, whereinthe composition comprises dexmedetomidine hydrochloride.

Embodiment 117. The method of any one of embodiments 113-116, whereinthe composition is administered sublingually or buccally.

Embodiment 118. The method of embodiment 117, wherein the composition isadministered sublingually in the form of a tablet, film, spray, gel ordrops.

Embodiment 119. The method of embodiment 117, wherein the composition isadministered buccally in the form of a film, patch or tablet.

Embodiment 120. The method of any one of embodiments 113-119, furthercomprising administering a second dose after a period of time rangingfrom about 30 minutes to about 12 hours.

Embodiment 121. The method of embodiment 120, wherein the additionaldose is about 60 μg or 90 μg.

Embodiment 122. The method of embodiment 120 or embodiment 121, whereinthe second dose is administered after a period of about 2 hours.

Embodiment 123. The method of any one of embodiments 113-122, whereinthe patient is in a fed state.

Embodiment 124. The method of any one of embodiments 113-122, whereinthe patient is in a fasted state.

Embodiment 125. The method of any one of embodiments 113-124, whereinagitation is significantly reduced within about 2 hours of administeringthe composition, as measured by a mean change in Positive and NegativeSyndrome Scale Excited Component (PEC) scores relative to baseline.

Embodiment 126. The method of embodiment 125, wherein the agitation issignificantly reduced within about 30 minutes to about 1 hour.

Embodiment 127. The method of embodiment 125 or embodiment 126, whereinthe patient experiences ≥40% decrease from baseline in PEC score.

Embodiment 128. The method of embodiment 127, wherein the patientexperiences ≥60% decrease from baseline in PEC score.

Embodiment 129. The method of any one of embodiments 125-128, whereinthe PEC score is ≥30% lower than placebo.

Embodiment 130. The method of embodiment 129, wherein the PEC score is≥60% lower than placebo.

Embodiment 131. The method of any one of embodiments 125-130, whereinthe mean change in PEC score is greater than −4 (i.e. a decrease of 4 ormore points) relative to baseline within 2 hours of administering thecomposition.

Embodiment 132. The method of embodiment 131, wherein mean change in PECscore is greater than −6 relative to baseline within 2 hours ofadministering the composition.

Embodiment 133. The method of embodiment 131, wherein mean change in PECscore is greater than −8 relative to baseline within 2 hours ofadministering the composition.

Embodiment 134. The method of any one of embodiments 125-133, whereinthe decrease in PEC score is maintained for at least six hours followingadministration of the composition.

Embodiment 135. The method of any one of embodiments 125-134, whereinthe mean change in PEC score is greater than or equal to −8 and ismaintained from 2 hours post administration up to at least about 6 hoursfollowing administration of the composition.

Embodiment 136. The method of any one of embodiments 113-135, whereinthe subject is treated without experiencing significant sedation.

Embodiment 137. The method of any one of embodiments 113-136, whereinthe subject is treated without experiencing clinically significantcardiovascular effects.

Embodiment 138. The method of any one of embodiments 113-137, whereinadministration of a single dose provides a mean C_(max) within the rangeof about 80% to about 125% of about 110 ng/L to about 400 ng/L.

Embodiment 139. The method of embodiment 138, wherein the mean C_(max)is within the range of about 80% to about 125% of about 238 ng/L.

Embodiment 140. The method of embodiment 138, wherein the mean C_(max)is about 238 ng/L

Embodiment 141. The method of any one of embodiments 113-140, whereinadministration of a single dose provides a mean AUC_(0-inf) within therange of about 80% to about 125% of about 590 hr*ng/L to about 4400hr*ng/L.

Embodiment 142. The method of embodiment 141, the mean AUC_(0-inf) iswithin the range of about 80% to about 125% of about 1810 ng*h/L.

Embodiment 143. The method of embodiment 141, wherein the meanAUC_(0-inf) is about 1810 ng*h/L.

Embodiment 144. The method of any one of embodiments 113-143 whereinadministration of a single dose provides a mean T_(max) within the rangeof about 80% to about 125% of about 1 hour to about 4 hours.

Embodiment 145. The method of embodiment 144, wherein the mean T_(max)is within the range of about 80% to about 125% of about 2 hours.

Embodiment 146. The method of embodiment 144, wherein the mean T_(max)is about 2 hours.

Embodiment 147. The method of any one of embodiments 113-146, whereinadministration of a single dose provides a geometric mean C_(max) withinthe range of about 80% to about 125% of about 110 ng/L to about 400ng/L.

Embodiment 148. The method of embodiment 147, wherein the geometric meanC_(max) is within the range of about 80% to about 125% of about 220ng/L.

Embodiment 149. The method of embodiment 147, wherein the geometric meanC_(max) is about 220 ng/L

Embodiment 150. The method of any one of embodiments 113-149, whereinadministration of a single dose provides a geometric mean AUC_(0-inf)within the range of about 80% to about 125% of about 590 hr*ng/L toabout 4400 hr*ng/L.

Embodiment 151. The method of embodiment 150, the geometric meanAUC_(0-inf) is within the range of about 80% to about 125% of about 1410ng*h/L.

Embodiment 152. The method of embodiment 150, wherein the geometric meanAUC_(0-inf) is about 1410 ng*h/L.

Embodiment 153. The method of any one of embodiments 113-152 whereinadministration of a single dose provides a geometric mean T_(max) withinthe range of about 80% to about 125% of about 1 hour to about 4 hours.

Embodiment 154. The method of embodiment 153, wherein the geometric meanT_(max) is within the range of about 80% to about 125% of about 2 hours.

Embodiment 155. The method of embodiment 153, wherein the geometric meanT_(max) is about 2 hours.

Embodiment 156. The method of any one of embodiments 113-155, whereinadministration of a single dose provides a median C_(max) within therange of about 80% to about 125% of about 110 ng/L to about 400 ng/L.

Embodiment 157. The method of embodiment 156, wherein the median C_(max)is within the range of about 80% to about 125% of about 230 ng/L.

Embodiment 158. The method of embodiment 156, wherein the median C_(max)is about 230 ng/L.

Embodiment 159. The method of any one of embodiments 113-158, whereinadministration of a single dose provides a median AUC_(0-inf) within therange of about 80% to about 125% of about 590 hr*ng/L to about 4400hr*ng/L.

Embodiment 160. The method of embodiment 159, the median AUC_(0-inf) iswithin the range of about 80% to about 125% of about 1180 ng*h/L.

Embodiment 161. The method of embodiment 141, wherein the medianAUC_(0-inf) is about 1810 ng*h/L.

Embodiment 162. The method of any one of embodiments 113-161 whereinadministration of a single dose provides a median T_(max) within therange of about 80% to about 125% of about 1 hour to about 4 hours.

Embodiment 163. The method of embodiment 162, wherein the median T_(max)is within the range of about 80% to about 125% of about 2 hours.

Embodiment 164. The method of embodiment 162, wherein the median T_(max)is about 2 hours.

Embodiment 165. The method of any one of embodiments 138-164, whereinthe pharmacokinetic parameters are non-steady state.

Embodiment 166. A method of treating agitation associated withschizophrenia or bipolar disorder, comprising administering a unit dosecomposition comprising about 180 μg of dexmedetomidine or apharmaceutically acceptable salt thereof to a human patient.

Embodiment 167. The method of embodiment 166, wherein the patient hasschizophrenia.

Embodiment 168. The method of embodiment 166 or embodiment 167, whereinthe patient has bipolar I disorder.

Embodiment 169. The method of any one of embodiments 166-168, whereinthe composition comprises dexmedetomidine hydrochloride.

Embodiment 170. The method of any one of embodiments 166-169, whereinthe composition is administered sublingually or buccally.

Embodiment 171. The method of embodiment 170, wherein the composition isadministered sublingually in the form of a tablet, film, spray, gel ordrops.

Embodiment 172. The method of embodiment 170, wherein the composition isadministered buccally in the form of a film, patch or tablet.

Embodiment 173. The method of any one of embodiments 166-172, furthercomprising administering a second dose after a period of time rangingfrom about 30 minutes to about 12 hours.

Embodiment 174. The method of embodiment 173, wherein the additionaldose is about 60 μg or 90 μg.

Embodiment 175. The method of embodiment 8 or embodiment 174, whereinthe second dose is administered after a period of about 2 hours.

Embodiment 176. The method of any one of embodiments 166-175, whereinthe patient is in a fed state.

Embodiment 177. The method of any one of embodiments 166-175, whereinthe patient is in a fasted state.

Embodiment 178. The method of any one of embodiments 166-177, whereinagitation is significantly reduced within about 2 hours of administeringthe composition, as measured by a mean change in Positive and NegativeSyndrome Scale Excited Component (PEC) scores relative to baseline.

Embodiment 179. The method of embodiment 178, wherein the agitation issignificantly reduced within about 30 minutes to about 1 hour.

Embodiment 180. The method of embodiment 178 or embodiment 179, whereinthe patient experiences ≥40% decrease from baseline in PEC score.

Embodiment 181. The method of embodiment 180, wherein the patientexperiences ≥60% decrease from baseline in PEC score.

Embodiment 182. The method of any one of embodiments 178-181, whereinthe PEC score is ≥30% lower than placebo.

Embodiment 183. The method of embodiment 182, wherein the PEC score is≥60% lower than placebo.

Embodiment 184. The method of any one of embodiments 178-183, whereinthe mean change in PEC score is greater than −4 (i.e. a decrease of 4 ormore points) relative to baseline within 2 hours of administering thecomposition.

Embodiment 185. The method of embodiment 184, wherein mean change in PECscore is greater than −6 relative to baseline within 2 hours ofadministering the composition.

Embodiment 186. The method of embodiment 184, wherein mean change in PECscore is greater than −8 relative to baseline within 2 hours ofadministering the composition.

Embodiment 187. The method of any one of embodiments 178-186, whereinthe decrease in PEC score is maintained for at least six hours followingadministration of the composition.

Embodiment 188. The method of any one of embodiments 178-187, whereinthe mean change in PEC score is greater than or equal to −8 and ismaintained from 2 hours post administration up to at least about 24hours following administration of the composition.

Embodiment 189. The method of any one of embodiments 166-188, whereinthe subject is treated without experiencing significant sedation.

Embodiment 190. The method of any one of embodiments 166-189, whereinthe subject is treated without experiencing clinically significantcardiovascular effects.

Embodiment 191. The method of any one of embodiments 166-190, whereinadministration of a single dose provides a mean C_(max) within the rangeof about 80% to about 125% of about 100 ng/L to about 800 ng/L.

Embodiment 192. The method of embodiment 191, wherein the mean C_(max)is within the range of about 80% to about 125% of about 440 ng/L

Embodiment 193. The method of embodiment 191, wherein the mean C_(max)is about 440 ng/L

Embodiment 194. The method of any one of embodiments 166-193, whereinadministration of a single dose provides a mean AUC_(0-inf) within therange of about 80% to about 125% of about 600 hr*ng/L to about 9500hr*ng/L.

Embodiment 195. The method of embodiment 194, the mean AUC_(0-inf) iswithin the range of about 80% to about 125% of about 3800 ng*h/L.

Embodiment 196. The method of embodiment 194, the mean AUC_(0-inf) isabout 3800 ng*h/L.

Embodiment 197. The method of any one of embodiments 166-196, hereinadministration of a single dose provides a mean T_(max) within the rangeof about 80% to about 125% of about 1 hour to about 8 hours.

Embodiment 198. The method of embodiment 197, wherein the mean T_(max)is within the range of about 80% to about 125% of about 2 hours.

Embodiment 199. The method of embodiment 197, wherein the mean T_(max)is about 2 hours.

Embodiment 200. The method of any one of embodiments 166-199, whereinadministration of a single dose provides a geometric mean C_(max) withinthe range of about 80% to about 125% of about 100 ng/L to about 800ng/L.

Embodiment 201. The method of embodiment 200, wherein the geometric meanC_(max) is within the range of about 80% to about 125% of about 380ng/L.

Embodiment 202. The method of embodiment 200, wherein the geometric meanC_(max) is about 380 ng/L.

Embodiment 203. The method of any one of embodiments 166-202, whereinadministration of a single dose provides a geometric mean AUC_(0-inf)within the range of about 80% to about 125% of about 600 hr*ng/L toabout 9500 hr*ng/L.

Embodiment 204. The method of embodiment 203, the geometric meanAUC_(0-inf) is within the range of about 80% to about 125% of about 2880ng*h/L.

Embodiment 205. The method of embodiment 203, wherein the geometric meanAUC_(0-inf) is about 2880 ng*h/L.

Embodiment 206. The method of any one of embodiments 166-205 whereinadministration of a single dose provides a geometric mean T_(max) withinthe range of about 80% to about 125% of about 1 hour to about 8 hours.

Embodiment 207. The method of embodiment 206, wherein the geometric meanT_(max) is within the range of about 80% to about 125% of about 2 hours.

Embodiment 208. The method of embodiment 206, wherein the geometric meanT_(max) is about 2 hours.

Embodiment 209. The method of any one of embodiments 166-208, whereinadministration of a single dose provides a median C_(max) within therange of about 80% to about 125% of about 110 ng/L to about 800 ng/L.

Embodiment 210. The method of embodiment 209, wherein the median C_(max)is within the range of about 80% to about 125% of about 485 ng/L.

Embodiment 211. The method of embodiment 209, wherein the median C_(max)is about 485 ng/L.

Embodiment 212. The method of any one of embodiments 166-211, whereinadministration of a single dose provides a median AUC_(0-inf) within therange of about 80% to about 125% of about 600 hr*ng/L to about 9500hr*ng/L.

Embodiment 213. The method of embodiment 212, the median AUC_(0-inf) iswithin the range of about 80% to about 125% of about 2900 ng*h/L.

Embodiment 214. The method of embodiment 194, wherein the medianAUC_(0-inf) is about 2900 ng*h/L.

Embodiment 215. The method of any one of embodiments 166-214 whereinadministration of a single dose provides a median T_(max) within therange of about 80% to about 125% of about 1 hour to about 8 hours.

Embodiment 216. The method of embodiment 215, wherein the median T_(max)is within the range of about 80% to about 125% of about 2 hours.

Embodiment 217. The method of embodiment 215, wherein the median T_(max)is about 2 hours.

Embodiment 218. The method of any one of embodiments 191-217, whereinthe pharmacokinetic parameters are non-steady state.

Embodiment 219. A method of treating agitation associated withschizophrenia or bipolar disorder, comprising administering a unit dosecomposition comprising about 120 μg to about 180 of dexmedetomidine or apharmaceutically acceptable salt thereof to a human patient.

Embodiment 220. The method of embodiment 219, wherein the patient hasschizophrenia.

Embodiment 221. The method of embodiment 219 or embodiment 220, whereinthe patient has bipolar I disorder.

Embodiment 222. The method of any one of embodiments 219-221, whereinthe composition comprises dexmedetomidine hydrochloride.

Embodiment 223. The method of any one of embodiments 219-222, whereinthe unit dose of dexmedetomidine is about 120 μg.

Embodiment 224. The method of any one of embodiments 219-222, whereinthe unit dose of dexmedetomidine is about 180 μg.

Embodiment 225. The method of any one of embodiments 219-224, whereinthe composition is administered sublingually or buccally.

Embodiment 226. The method of embodiment 225, wherein the composition isadministered sublingually in the form of a tablet, film, spray, gel ordrops.

Embodiment 227. The method of embodiment 225, wherein the composition isadministered buccally in the form of a film, patch or tablet.

Embodiment 228. The method of any one of embodiments 219-227, furthercomprising administering a second dose after a period of time rangingfrom about 30 minutes to about 12 hours.

Embodiment 229. The method of embodiment 228, wherein the additionaldose is about 60 μg or 90 μg.

Embodiment 230. The method of embodiment 228 or embodiment 229, whereinthe second dose is administered after a period of about 2 hours.

Embodiment 231. The method of any one of embodiments 219-230, whereinagitation is significantly reduced within about 2 hours of administeringthe composition, as measured by a mean change in Positive and NegativeSyndrome Scale Excited Component (PEC) scores relative to baseline.

Embodiment 232. The method of embodiment 231, wherein the agitation issignificantly reduced within about 30 minutes to about 1 hour.

Embodiment 233. The method of embodiment 231 or embodiment 232, whereinthe patient experiences ≥40% decrease from baseline in PEC score.

234. The method of embodiment 233, wherein the patient experiences ≥60%decrease from baseline in PEC score.

Embodiment 235. The method of any one of embodiments 231-234, whereinthe PEC score is ≥30% lower than placebo.

Embodiment 236. The method of embodiment 235, wherein the PEC score is≥60% lower than placebo.

Embodiment 237. The method of any one of embodiments 231-236, whereinthe mean change in PEC score is greater than −4 (i.e. a decrease of 4 ormore points) relative to baseline within 2 hours of administeringdexmedetomidine.

Embodiment 238. The method of embodiment 237, wherein mean change in PECscore is greater than −6 relative to baseline within 2 hours ofadministering the composition.

Embodiment 239. The method of embodiment 237, wherein mean change in PECscore is greater than −8 relative to baseline within 2 hours ofadministering the composition.

Embodiment 240. The method of any one of embodiments 231-239, whereinthe decrease in PEC score is maintained for at least six hours followingadministration of the composition.

Embodiment 241. The method of any one of embodiments 231-240, whereinthe mean change in PEC score is greater than or equal to −8 and ismaintained from 2 hours post administration up to at least about 24hours following administration of the composition.

Embodiment 242. The method of any one of embodiments 219-241, whereinthe subject is treated without experiencing significant sedation.

Embodiment 243. The method of any one of embodiments 219-242, whereinthe subject is treated without experiencing clinically significantcardiovascular effects.

Embodiment 244. The method of any one of embodiments 219-243, whereinadministration of a single dose provides a mean peak plasmaconcentration (C_(max)) within the range of about 80% to about 125% ofabout 100 ng/L to about 800 ng/L.

Embodiment 245. The method of embodiment 244, wherein the mean C_(max)is within the range of about 80% to about 125% of about 200 ng/L toabout 500 ng/L.

Embodiment 246. The method of embodiment 244, wherein the mean C_(max)is within the range of about 80% to about 125% of 230 ng/L to about 440ng/L.

Embodiment 247. The method of any one of embodiments 219-246, whereinadministration of a single dose provides a mean area under the curve(AUC)_(0-inf) within the range of about 80% to about 125% of about 590hr*ng/L to about 9500 hr*ng/L.

Embodiment 248. The method of embodiment 247, wherein the meanAUC_(0-inf) is within the range of about 80% to about 125% of 1400ng*h/L to about 4000 hr*ng/L.

Embodiment 249. The method of embodiment 247, wherein the meanAUC_(0-inf) is within the range of about 80% to about 125% of 1800ng*h/L to about 3800 ng*h/L.

Embodiment 250. The method of any one of embodiments 219-249 whereinadministration of a single dose provides a mean time to peak plasmaconcentration (T_(max)) within the range of about 80% to about 125% ofabout 1 hour to about 8 hours.

Embodiment 251. The method of embodiment 250, wherein the mean T_(max)is within the range of about 80% to about 125% of about hours.

Embodiment 252. The method of embodiment 250, wherein the mean T_(max)is about 2 hours.

Embodiment 253. The method of any one of embodiments 244-252, whereinthe pharmacokinetic parameters are non-steady state.

Embodiment 254. The method of any one of embodiments 219-253, whereinthe patient is in a fed state.

Embodiment 255. The method of any one of embodiments 219-253, whereinthe patient is in a fasted state.

Embodiment 256. A method of treating or ameliorating opioid withdrawalsymptoms, comprising administering a composition comprisingdexmedetomidine or a pharmaceutically acceptable salt thereof to a humanpatient in need thereof, wherein the patient is at least 18 years andwherein the period of withdrawal is up to 14 days.

Embodiment 257. The method of embodiment 256, wherein the treatmentcomprises reducing the period of opioid withdrawal.

Embodiment 258. The method of embodiment 256 or embodiment 257, whereinthe treating or ameliorating is measured by the Clinical OpiateWithdrawal Scale (COWS) and/or Short Opiate Withdrawal Scale of Gossop(SOWS-Gossop) score.

Embodiment 259. The method of any one of embodiments 256-258, whereinthe composition is administered twice daily.

Embodiment 260. The method of any one of embodiments 256-259, whereinthe composition comprises a dose range of dexmedetomidine or apharmaceutically acceptable salt thereof of between about 30 μg andabout 200 μg.

Embodiment 261. The method of any one of embodiments 256-260, whereinthe composition comprises a unit dose of about 30 μg, about 60 μg, about90 μg, about 120 μg, or 180 μg of dexmedetomidine or a pharmaceuticallyacceptable salt thereof.

Embodiment 262. The method of any one of embodiments 256-261, whereinthe period of withdrawal is up to 13 days, 12 days, 11 days, 10 days, 9days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days.

Embodiment 263. The method of any one of embodiments 256-262, whereinthe opioid is selected from the group comprising of fentanyl, morphine,codeine, heroin, oxycodone, hydrocodone, alfentanil carfentanil,tramadol, hydromorphone, buprenorphine, naloxone, naltrexone,remifentanil butorphanol, meperidine, methadone, dextropropoxyphene(propoxyphene) thebaine, sufentanil and pentazocine.

Embodiment 264. The method of embodiment 263, wherein the opioid isselected from the group comprising of fentanyl.

Embodiment 265. The method of any one of embodiments 256-262, whereinthe opioid had been administered for amount of time longer than neonatetreatment prior to withdrawal.

Embodiment 266. The method of any one of embodiments 256-265, whereinthe composition is administered sublingually, buccally, orally,intranasally or parenterally.

Embodiment 267. The method of embodiments any one of embodiments256-266, wherein the composition is administered sublingually in theform of a tablet, film, spray, gel or drops.

Embodiment 268. The method of embodiment 267, wherein the composition isadministered sublingually in the form of a film.

Embodiment 269. The method of any one of embodiments 256-266, whereinthe composition is administered buccally in the form of a film, patch ortablet.

Embodiment 270. The method of embodiment 269, wherein the composition isadministered buccally in the form of a film.

Embodiment 271. The method of any one of embodiments 256-270, whereinthe patient is treated without also inducing clinically significantcardiovascular effects.

Embodiment 272. The method of any one of embodiments 256-271 wherein asingle dose of a composition comprising about 180 μg dexmedetomidine ora pharmaceutically acceptable salt thereof is effective for up to atleast about 24 hours.

Embodiment 273. The method of any one of embodiments 256-272, whereinthe composition comprises dexmedetomidine hydrochloride.

Embodiment 274. The method of any one of embodiments 256-273, whereinthe opioid withdrawal symptom is agitation.

Embodiment 275. The method of any one of embodiments 256-274, whereinthe composition is administered twice daily for 7 days.

Embodiment 276. A pharmaceutical composition comprising from about 20 μgto about 240 μg dexmedetomidine or a pharmaceutically acceptable saltthereof.

Embodiment 277. The composition of embodiment 276, whereindexmedetomidine is present as dexmedetomidine hydrochloride.

Embodiment 278. The composition of embodiment 276 or embodiment 277,wherein the dose of dexmedetomidine is about 120 μg.

Embodiment 279. The composition of any one of embodiments 276-278,wherein the dose of dexmedetomidine is about 180 μg.

Embodiment 280. The composition of any one of embodiments 276-279,wherein the composition is formulated for sublingual or buccaladministration.

Embodiment 281. The composition of embodiment 280, wherein thecomposition is formulated for sublingual administration in the form of atablet, film, spray, gel or drops.

Embodiment 282. The composition of embodiment 280, wherein thecomposition is formulated for buccal administration in the form of afilm, patch or tablet.

Embodiment 283. The composition of any one of embodiments 276-282,wherein if administered to a patient having agitation associated withschizophrenia or bipolar disorder, the agitation is significantlyreduced within about 2 hours of administering the composition asmeasured by a mean change in Positive and Negative Syndrome ScaleExcited Component (PEC) scores relative to baseline.

Embodiment 284. The composition of embodiment 283, wherein the agitationis significantly reduced within about 30 minutes to about 1 hour.

Embodiment 285. The composition of embodiment 283 or embodiment 284,wherein the patient experiences ≥40% decrease from baseline in PECscore.

Embodiment 286. The composition of embodiment 285, wherein the patientexperiences ≥60% decrease from baseline in PEC score.

Embodiment 287. The composition of any one of embodiments 283-286,wherein the PEC score is ≥30% lower than placebo.

Embodiment 288. The composition of embodiment 287, wherein the PEC scoreis ≥60% lower than placebo.

Embodiment 289. The composition of any one of embodiments 283-288,wherein the mean change in PEC score is greater than −4 (i.e. a decreaseof 4 or more points) relative to baseline within 2 hours ofadministering the composition.

Embodiment 290. The composition of embodiment 289, wherein mean changein PEC score is greater than −6 relative to baseline within 2 hours ofadministering the composition.

Embodiment 291. The composition of embodiment 289, wherein mean changein PEC score is greater than −8 relative to baseline within 2 hours ofadministering the composition.

Embodiment 292. The composition of any one of embodiments 283-291,wherein the decrease in PEC score is maintained for at least six hoursfollowing administration of the composition.

Embodiment 293. The composition of any one of embodiments 283-292,wherein the mean change in PEC score is greater than or equal to −8 andis maintained from 2 hours post administration up to at least about 24hours following administration of the composition.

Embodiment 294. The composition of any one of embodiments 283-293,wherein the subject is treated without experiencing significantsedation.

Embodiment 295. The composition of any one of embodiments 283-294,wherein the subject is treated without experiencing clinicallysignificant cardiovascular effects.

Embodiment 296. The composition of any one of embodiments 276-295,wherein if administered to a patient having schizophrenia or bipolardisorder, a single dose provides a mean Cmax within the range of about80% to about 125% of about 100 ng/L to about 800 ng/L.

Embodiment 297. The composition of embodiment 296, wherein the geometricmean C_(max) is from about 200 ng/L to about 400 ng/L.

Embodiment 298. The composition of embodiment 296, wherein the meanC_(max) is within the range of about 80% to about 125% of 230 ng/L toabout 440 ng/L.

Embodiment 299. The composition of any one of embodiments 276-298,wherein if administered to a patient having schizophrenia or bipolardisorder, a single dose provides a mean a AUC_(0-inf) within the rangeof about 80% to about 125% of about 590 hr*ng/L to about 9500 hr*ng/L.

Embodiment 300. The composition of embodiment 299, wherein the meanAUC_(0-inf) is within the range of about 80% to about 125% of 1400ng*h/L to about 4000 hr*ng/L.

Embodiment 301. The composition of embodiment 299, wherein the meanAUC_(0-inf) is within the range of about 80% to about 125% of 1800ng*h/L to about 3800 ng*h/L.

Embodiment 302. The composition of any one of embodiments 276-301,wherein if administered to a patient having schizophrenia or bipolardisorder, a single dose provides a mean time to peak plasmaconcentration (T_(max)) within the range of about 80% to about 125% ofabout 1 hour to about 8 hours.

Embodiment 303. The composition of embodiment 302, wherein the meanT_(max) is within the range of about 80% to about 125% of about hours.

Embodiment 304. The composition of embodiment 302, wherein the meanT_(max) is about 2 hours.

Embodiment 305. The composition of any one of embodiments 296-304,wherein the pharmacokinetic parameters are non-steady state.

Embodiment 306. The composition of any one of embodiments 283-305,wherein the patient is in a fed state.

Embodiment 307. The composition of any one of embodiments 283-305,wherein the patient is in a fasted state.

Embodiment 308. A method of treating agitation associated withschizophrenia or bipolar disorder, comprising administering a unit dosecomposition comprising dexmedetomidine or a pharmaceutically acceptablesalt thereof to a human patient, wherein the dose provides one or moreof the following pharmacokinetic parameters:

-   -   (1) a mean C_(max) within the range of about 80% to about 125%        of about 110 ng/L to about 400 ng/L; and/or    -   (2) a mean AUC_(0-inf) within the range of about 80% to about        125% of about 590 hr*ng/L to about 4400 hr*ng/L; and/or    -   (3) a mean T_(max) within the range of about 80% to about 125%        of about 1 hour to about 4 hours.

Embodiment 309. The method of embodiment 308, wherein the patient hasschizophrenia.

Embodiment 310. The method of embodiment 308 or embodiment 309, whereinthe patient has bipolar I disorder.

Embodiment 311. The method of any one of embodiments 308-310, whereinthe composition comprises dexmedetomidine hydrochloride.

Embodiment 312. The method of any one of embodiments 308-311, whereinthe composition is administered sublingually or buccally.

Embodiment 313. The method of embodiment 312, wherein the composition isadministered sublingually in the form of a tablet, film, spray, gel ordrops.

Embodiment 314. The method of embodiment 312, wherein the composition isadministered buccally in the form of a film, patch or tablet.

Embodiment 315. The method of any one of embodiments 308-314, furthercomprising administering a second dose after a period of time rangingfrom about 30 minutes to about 12 hours.

Embodiment 316. The method of embodiment 315, wherein the additionaldose is about 60 μg or 90 μg.

Embodiment 317. The method of embodiment 315 or embodiment 316, whereinthe second dose is administered after a period of about 2 hours.

Embodiment 318. The method of any one of embodiments 308-317, whereinthe patient is in a fed state.

Embodiment 319. The method of any one of embodiments 308-317, whereinthe patient is in a fasted state.

Embodiment 320. The method of any one of embodiments 308-319, whereinagitation is significantly reduced within about 2 hours of administeringthe composition, as measured by a mean change in Positive and NegativeSyndrome Scale Excited Component (PEC) scores relative to baseline.

Embodiment 321. The method of embodiment 320, wherein the agitation issignificantly reduced within about 30 minutes to about 1 hour.

Embodiment 322. The method of embodiment 320 or embodiment 321, whereinthe patient experiences ≥40% decrease from baseline in PEC score.

Embodiment 323. The method of embodiment 322, wherein the patientexperiences ≥60% decrease from baseline in PEC score.

Embodiment 324. The method of any one of embodiments 320-323, whereinthe PEC score is ≥30% lower than placebo.

Embodiment 325. The method of embodiment 324, wherein the PEC score is≥60% lower than placebo.

Embodiment 326. The method of any one of embodiments 320-325, whereinthe mean change in PEC score is greater than −4 (i.e. a decrease of 4 ormore points) relative to baseline within 2 hours of administering thecomposition.

Embodiment 327. The method of embodiment 326, wherein mean change in PECscore is greater than −6 relative to baseline within 2 hours ofadministering the composition.

Embodiment 328. The method of embodiment 326, wherein mean change in PECscore is greater than −8 relative to baseline within 2 hours ofadministering the composition.

Embodiment 329. The method of any one of embodiments 320-328, whereinthe decrease in PEC score is maintained for at least six hours followingadministration of the composition.

Embodiment 330. The method of any one of embodiments 320-329, whereinthe mean change in PEC score is greater than or equal to −8 and ismaintained from 2 hours post administration up to at least about 6 hoursfollowing administration of the composition.

Embodiment 331. The method of any one of embodiments 308-330, whereinthe subject is treated without experiencing significant sedation.

Embodiment 332. The method of any one of embodiments 308-331, whereinthe subject is treated without experiencing clinically significantcardiovascular effects.

Embodiment 333. The method of any one of embodiments 308-332 wherein twoor more of the pharmacokinetic parameters are present.

Embodiment 334. The method of any one of embodiments 308-333, whereinall three of the pharmacokinetic parameters are present.

Embodiment 335. The method of any one of embodiments 308-334, whereinthe mean C_(max) is within the range of about 80% to about 125% of about238 ng/L.

Embodiment 336. The method of embodiment 335, wherein the mean C_(max)is about 238 ng/L

Embodiment 337. The method of any one of embodiments 308-336, whereinadministration of a single dose provides a mean AUC_(0-inf) within therange of about 80% to about 125% of about 1810 ng*h/L.

Embodiment 338. The method of embodiment 337, wherein the mean about1810 ng*h/L.

Embodiment 339. The method of any one of embodiments 308-338 whereinadministration of a single dose provides a mean T_(max) within the rangeof about 80% to about 125% of about 2 hours.

Embodiment 340. The method of embodiment 339, wherein the mean T_(max)is about 2 hours.

Embodiment 341. The method of any one of embodiments 308-340, whereinthe pharmacokinetic parameters are non-steady state.

Embodiment 342. A method of treating agitation associated withschizophrenia or bipolar disorder, comprising administering a unit dosecomposition comprising dexmedetomidine or a pharmaceutically acceptablesalt thereof to a human patient, wherein the dose provides one or moreof the following pharmacokinetic parameters:

-   -   (1) a mean C_(max) within the range of about 80% to about 125%        of about 100 ng/L to about 800 ng/L; and/or    -   (2) a mean AUC_(0-inf) within the range of about 80% to about        125% of about 600 hr*ng/L to about 9500 hr*ng/L; and/or    -   (3) a mean T_(max) within the range of about 80% to about 125%        of about 1 hour to about 8 hours.

Embodiment 343. The method of embodiment 342, wherein the patient hasschizophrenia.

Embodiment 344. The method of embodiment 342 or embodiment 343, whereinthe patient has bipolar I disorder.

Embodiment 345. The method of any one of embodiments 342-344, whereinthe composition comprises dexmedetomidine hydrochloride.

Embodiment 346. The method of any one of embodiments 342-345, whereinthe composition is administered sublingually or buccally.

Embodiment 347. The method of embodiment 346, wherein the composition isadministered sublingually in the form of a tablet, film, spray, gel ordrops.

Embodiment 348. The method of embodiment 346, wherein the composition isadministered buccally in the form of a film, patch or tablet.

Embodiment 349. The method of any one of embodiments 342-348, furthercomprising administering a second dose after a period of time rangingfrom about 30 minutes to about 12 hours.

Embodiment 350. The method of embodiment 349, wherein the additionaldose is about 60 μg or 90 μg.

Embodiment 351. The method of embodiment 349 or embodiment 350, whereinthe second dose is administered after a period of about 2 hours.

Embodiment 352. The method of any one of embodiments 342-351, whereinthe patient is in a fed state.

Embodiment 353. The method of any one of embodiments 342-351, whereinthe patient is in a fasted state.

Embodiment 354. The method of any one of embodiments 342-353, whereinagitation is significantly reduced within about 2 hours of administeringthe composition, as measured by a mean change in Positive and NegativeSyndrome Scale Excited Component (PEC) scores relative to baseline.

Embodiment 355. The method of embodiment 354, wherein the agitation issignificantly reduced within about 30 minutes to about 1 hour.

Embodiment 356. The method of embodiment 354 or embodiment 355, whereinthe patient experiences ≥40% decrease from baseline in PEC score.

Embodiment 357. The method of embodiment 356, wherein the patientexperiences ≥60% decrease from baseline in PEC score.

Embodiment 358. The method of any one of embodiments 354-357, whereinthe PEC score is ≥30% lower than placebo.

Embodiment 359. The method of embodiment 358, wherein the PEC score is≥60% lower than placebo.

Embodiment 360. The method of any one of embodiments 354-359, whereinthe mean change in PEC score is greater than −4 (i.e. a decrease of 4 ormore points) relative to baseline within 2 hours of administering thecomposition.

Embodiment 361. The method of embodiment 360, wherein mean change in PECscore is greater than −6 relative to baseline within 2 hours ofadministering the composition.

Embodiment 362. The method of embodiment 360, wherein mean change in PECscore is greater than −8 relative to baseline within 2 hours ofadministering the composition.

Embodiment 363. The method of any one of embodiments 354-362, whereinthe decrease in PEC score is maintained for at least six hours followingadministration of the composition.

Embodiment 364. The method of any one of embodiments 354-363, whereinthe mean change in PEC score is greater than or equal to −8 and ismaintained from 2 hours post administration up to at least about 6 hoursfollowing administration of the composition.

Embodiment 365. The method of any one of embodiments 342-364, whereinthe subject is treated without experiencing significant sedation.

Embodiment 366. The method of any one of embodiments 342-365, whereinthe subject is treated without experiencing clinically significantcardiovascular effects.

Embodiment 367. The method of any one of embodiments 342-366 wherein twoor more of the pharmacokinetic parameters are present.

Embodiment 368. The method of any one of embodiments 342-367, whereinall three of the pharmacokinetic parameters are present.

Embodiment 369. The method of any one of embodiments 342-368, whereinthe mean C_(max) is within the range of about 80% to about 125% of about440 ng/L.

Embodiment 370. The method of embodiment 369, wherein the mean C_(max)is about 440 ng/L

Embodiment 371. The method of any one of embodiments 342-370, whereinadministration of a single dose provides a mean AUC_(0-inf) within therange of about 80% to about 125% of about 3800 ng*h/L.

Embodiment 372. The method of embodiment 371, wherein the mean about3800 ng*h/L.

Embodiment 373. The method of any one of embodiments 342-372 whereinadministration of a single dose provides a mean T_(max) within the rangeof about 80% to about 125% of about 2 hours.

Embodiment 374. The method of embodiment 373, wherein the mean T_(max)is about 2 hours.

Embodiment 375. The method of any one of embodiments 342-374, whereinthe pharmacokinetic parameters are non-steady state.

Embodiment 376. The method of any of the preceding embodiments, whereinagitation is reduced to a 1 (very much improved) or 2 (much improved)within 2 hours of administering the composition, as measured by theClinical Global Impression—Improvement Scale.

Embodiment 377. The method of embodiment 376, wherein the agitation isreduced within about 30 minutes to about 1 hour.

Embodiment 378. The method of embodiment 377, wherein the agitation isreduced within about 30 minutes.

Embodiment 379. The method of any one of embodiments 376-378, whereinthe reduction in agitation is reduced to a 1 (very much improved).

Embodiment 380. The method of embodiment any one of embodiments 376-379,wherein the reduction in agitation is maintained for greater than about2 hours.

Embodiment 381. The method of any one of embodiments 376-380, whereinthe reduction in agitation is maintained for greater than about 4 hours.

Embodiment 382. The method of any one of embodiments 376-381, whereinthe reduction in agitation is maintained for greater than about 6 hours.

Embodiment 383. The method of any one of embodiments 376-382, whereinthe reduction in agitation is maintained for greater than about 8 hours.

Embodiment 384. The method of any one of embodiments 376-383, whereinthe composition comprises 120 μg of dexmedetomidine.

Embodiment 385. The method of any one of embodiments 376-383, whereinthe composition comprises 180 μg of dexmedetomidine.

Embodiment 386. The method of any one of embodiments 376-385, whereinthe patient has schizophrenia.

Embodiment 387. The method of any one of embodiments 376-386, whereinthe patient has bipolar disorder.

Embodiment 388. The method of any of the preceding embodiments, whereinagitation is reduced to a 3 (mild agitation) or 4 (normal behavior)within 2 hours of administering the composition, as measured by theAgitation-Calmness Evaluation Scale (ACES).

Embodiment 389. The method of embodiment 388, wherein the agitation isreduced within about 30 minutes to about 1 hour.

Embodiment 390. The method of embodiment 388 or embodiment 389, whereinthe reduction in agitation is reduced to a 4 (normal behavior).

Embodiment 391. The method of any one of embodiments 388-390, whereinthe reduction in agitation is maintained for greater than about 2 hours.

Embodiment 392. The method of any one of embodiments 388-391, whereinthe reduction in agitation is maintained for greater than about 4 hours.

Embodiment 393. The method of any one of embodiments 388-392, whereinthe reduction in agitation is maintained for greater than about 6 hours.

Embodiment 394. The method of any one of embodiments 388-393, whereinthe reduction in agitation is maintained for greater than about 8 hours.

Embodiment 395. The method of any one of embodiments 388-394, whereinthe composition comprises 120 μg of dexmedetomidine.

Embodiment 396. The method of any one of embodiments 388-394, whereinthe composition comprises 180 μg of dexmedetomidine.

Embodiment 397. The method of any one of embodiments 388-396, whereinthe patient has schizophrenia.

Embodiment 398. The method of any one of embodiments 388-397, whereinthe patient has bipolar disorder.

Embodiment 399. The method of any of the preceding embodiments, whereinthe patient experiences a ≥40 reduction in agitation, as measured by thePEC Scale.

Embodiment 400. The method of embodiment 399, wherein the agitation isreduced within about 30 minutes to about 1 hour.

Embodiment 401. The method of embodiment 399 or embodiment 400, whereinthe patient experiences a ≥60 reduction in agitation.

Embodiment 402. The method any one of embodiments 399-401, wherein thepatient experiences a ≥80 reduction in agitation.

Embodiment 403. The method of any one of embodiments 399-402, whereinthe reduction in agitation is maintained for greater than about 2 hours.

Embodiment 404. The method of any one of embodiments 399-403, whereinthe reduction in agitation is maintained for greater than about 4 hours.

Embodiment 405. The method of any one of embodiments 399-404, whereinthe reduction in agitation is maintained for greater than about 6 hours.

Embodiment 406. The method of any one of embodiments 399-405, whereinthe reduction in agitation is maintained for greater than about 8 hours.

Embodiment 407. The method of any one of embodiments 399-406, whereinthe composition comprises 120 μg of dexmedetomidine.

Embodiment 408. The method of any one of embodiments 399-406, whereinthe composition comprises 180 μg of dexmedetomidine.

Embodiment 409. The method of any one of embodiments 399-408, whereinthe patient has schizophrenia.

Embodiment 410. The method of any one of embodiments 399-409, whereinthe patient has bipolar disorder.

Embodiment 411. A method of achieving a PEC score reduction in agitationfor a sustained period of time in a subject with bipolar orschizophrenic subject comprising administering to the subject apharmaceutical composition comprising dexmedetomidine or apharmaceutically acceptable salt thereof at a dose of about 120 mcg toabout 180 mcg wherein the PEC score reduction is about −8 to about −10and wherein the sustained period is about 2 hours to about 6 hours.

Embodiment 412. The method of embodiment 411, wherein the compositioncomprises dexmedetomidine hydrochloride.

Embodiment 413. The method of embodiment 411 or 412, comprisingdexmedetomidine or a pharmaceutically acceptable salt thereof at a doseof about 120 mcg.

Embodiment 414. The method of embodiment 411 or 412, comprisingdexmedetomidine or a pharmaceutically acceptable salt thereof at a doseof about 180 mcg.

Embodiment 415. The method according to any one of embodiments 411 to414, wherein the sustained period is about 4 hours.

Embodiment 416. The method according to embodiment 415, wherein thesustained period is about 6 hours.

Embodiment 417. The method according to any one of embodiments 411-416,wherein the PEC score reduction is about −10.

Embodiment 418. A method of achieving an ACES score improvement for asustained period of time in a subject with bipolar or schizophrenicsubject comprising administering to the subject a pharmaceuticalcomposition comprising dexmedetomidine or a pharmaceutically acceptablesalt thereof at a dose of about 120 mcg to about 180 mcg wherein theACES score is improved to about 3 to about 4 and wherein the sustainedperiod is about 2 hours to about 6 hours.

Embodiment 419. The method of embodiment 418, wherein the compositioncomprises dexmedetomidine hydrochloride.

Embodiment 420. The method of embodiment 418 or 419, comprisingdexmedetomidine or a pharmaceutically acceptable salt thereof at a doseof about 120 mcg.

Embodiment 421. The method of embodiment 418 or 419, comprisingdexmedetomidine or a pharmaceutically acceptable salt thereof at a doseof about 180 mcg.

Embodiment 422. The method according to any one of embodiments 418 to421, wherein the sustained period is about 4 hours.

Embodiment 423. The method according to embodiment 422, wherein thesustained period is about 6 hours.

Embodiment 424. The method according to any one of embodiments 418-423,wherein the ACES score is about 4.

Embodiment 425. A method of achieving an CGI-I score improvement for asustained period of time in a subject with bipolar or schizophrenicsubject comprising administering to the subject a pharmaceuticalcomposition comprising dexmedetomidine or a pharmaceutically acceptablesalt thereof at a dose of about 120 mcg to about 180 mcg wherein theCGI-I score is improved to about a 1 (very much improved) or about a 2(much improved) and wherein the sustained period is about 2 hours toabout 6 hours.

Embodiment 426. The method of embodiment 425, wherein the compositioncomprises dexmedetomidine hydrochloride.

Embodiment 427. The method of embodiment 425 or 426, comprisingdexmedetomidine or a pharmaceutically acceptable salt thereof at a doseof about 120 mcg.

Embodiment 428. The method of embodiment 425 or 426, comprisingdexmedetomidine or a pharmaceutically acceptable salt thereof at a doseof about 180 mcg.

Embodiment 429. The method according to any one of embodiments 425 to428, wherein the sustained period is about 4 hours.

Embodiment 430. The method according to embodiment 425, wherein thesustained period is about 6 hours.

Embodiment 431 The method according to any one of embodiments 425-430,wherein the CGI-I score is about 1.

Embodiment 432. The method of any one of embodiments 110 to 112, whereineach water-soluble polymer is hydroxypropyl cellulose.

Embodiment 433. The method of any one of embodiments 103 to 113, whereinthe dexmedetomidine or a pharmaceutically acceptable salt thereof isdexmedetomidine hydrochloride.

Embodiment 434. The method of any relevant preceding embodiments,wherein dexmedetomidine hydrochloride is administered as a film, whereinsaid film is a self-supporting, dissolvable, film, comprising:

-   -   (a) a composition comprising:        -   (i) dexmedetomidine hydrochloride;        -   (ii) hydroxypropyl cellulose (40,000 MW); and        -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate comprising:        -   (i) hydroxypropyl cellulose (40,000 MW);        -   (ii) hydroxypropyl cellulose (140,000 MW);        -   (iii) hydroxypropyl cellulose (370,000 MW); and        -   (iv) polyethylene oxide (600,000 MW);            -   wherein the composition of part (a) is present on the                surface of the film substrate (b).

Embodiment 435. The method of any relevant preceding embodiment, whereindexmedetomidine hydrochloride thereof is administered as a film, whereinsaid film is a self-supporting, dissolvable, film, comprising:

-   -   (a) a composition consisting essentially of:        -   (i) dexmedetomidine hydrochloride;        -   (ii) hydroxypropyl cellulose (40,000 MW); and        -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:        -   (i) hydroxypropyl cellulose (40,000 MW);        -   (ii) hydroxypropyl cellulose (140,000 MW);        -   (iii) hydroxypropyl cellulose (370,000 MW); and        -   (iv) polyethylene oxide (600,000 MW);    -   wherein the composition of part (a) is present on the surface of        the film substrate (b).

Embodiment 436. The method of embodiment 434 or embodiment 435, whereindexmedetomidine hydrochloride is present at about 0.1% to about 0.2% w/wof the total film weight, hydroxypropyl cellulose (40,000 MW) is presentat about 4% to about 6% w/w of the total film weight, hydroxypropylcellulose (140,000 MW) is present at about 4% to about 6% w/w of thetotal film weight, hydroxypropyl cellulose (370,000 MW) is present atabout 27% to about 30% w/w of the total film weight, and polyethyleneoxide (600,000 MW) is present at about 55% to about 60% w/w of the totalfilm weight.

Embodiment 437. A self-supporting, dissolvable, film, comprising:

-   -   (a) a composition consisting essentially of:        -   (i) about 180 μg of dexmedetomidine hydrochloride;        -   (ii) hydroxypropyl cellulose (40,000 MW); and        -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:        -   (i) hydroxypropyl cellulose (40,000 MW);        -   (ii) hydroxypropyl cellulose (140,000 MW);        -   (iii) hydroxypropyl cellulose (370,000 MW); and        -   (iv) polyethylene oxide (600,000 MW);            -   wherein the composition of part (a) is present on the                surface of the film substrate (b).

Embodiment 438. The film of embodiment 437 wherein dexmedetomidinehydrochloride is present at about 0.1% to about 0.2% w/w of the totalfilm weight, hydroxypropyl cellulose (40,000 MW) is present at about 4%to about 6% w/w of the total film weight, hydroxypropyl cellulose(140,000 MW) is present at about 4% to about 6% w/w of the total filmweight, hydroxypropyl cellulose (370,000 MW) is present at about 27% toabout 30% w/w of the total film weight, and polyethylene oxide (600,000MW) is present at about 55% to about 60% w/w of the total film weight.

Embodiment 439. A self-supporting, dissolvable, film, comprising:

-   -   (a) a composition consisting essentially of:        -   (i) about 120 μg of dexmedetomidine hydrochloride;        -   (ii) hydroxypropyl cellulose (40,000 MW); and        -   (iii) hydroxypropyl cellulose (140,000 MW); and    -   (b) a film substrate consisting essentially of:        -   (i) hydroxypropyl cellulose (40,000 MW);        -   (ii) hydroxypropyl cellulose (140,000 MW);        -   (iii) hydroxypropyl cellulose (370,000 MW); and        -   (iv) polyethylene oxide (600,000 MW);            wherein the composition of part (a) is present on the            surface of the film substrate (b).

Embodiment 440. The film of embodiment 439 wherein dexmedetomidinehydrochloride is present at about 0.1% to about 0.2% w/w of the totalfilm weight, hydroxypropyl cellulose (40,000 MW) is present at about 4%to about 6% w/w of the total film weight, hydroxypropyl cellulose(140,000 MW) is present at about 4% to about 6% w/w of the total filmweight, hydroxypropyl cellulose (370,000 MW) is present at about 27% toabout 30% w/w of the total film weight, and polyethylene oxide (600,000MW) is present at about 55% to about 60% w/w of the total film weight.

Embodiment 441. The method of any of relevant preceding embodiments,where dexmedetomidine or a pharmaceutically acceptable salt thereof isadministered as a sublingual spray, sublingual drop, sublingual gel,buccal tablet or sublingual tablet as embodied in table 1, table 2,table 3, table 4 or table 5 respectively.

EXAMPLE 1: DEXMEDETOMIDINE SUBLINGUAL FILM FORMULATION

TABLE 6 Dexmedetomidine deposited on the surface of a polymer matrixfilm composition Concentration Concentration g/100 g g/100 g Ingredients(10 μg film) (20 μg film) Function Drug-containing compositionDexmedetomidine hydrochloride 0.136 0.267 Active agent Hydroxypropylcellulose, HPC-SSL (MW = 0.301 0.593 Film former 40,000) Hydroxypropylcellulose (MW = 140,000) 0.301 0.593 Film former FD&C Blue #1 Granular0.002 0.004 Color Ethyl Alcohol as a solvent qs qs Solvent Polymermatrix composition Hydroxypropyl cellulose (MW = 140,000) 4.803 4.768Film former Hydroxypropyl cellulose, HPC-SSL (MW = 4.803 4.768 Filmformer 40,000) Hydroxypropyl cellulose (MW = 370,000) 28.809 28.601 Filmformer Fast Emerald Green Shade (NO. 06507) 0.129 0.128 Color Sucralose,USP-NF Grade 0.993 0.985 Sweetener Peppermint Oil, NF 2.104 2.089 FlavorPolyethylene oxide (Sentry Polyox 57.618 57.202 Film former & WSR 205LEO NF) (MW = 600,000) Mucoadhesive Water as a solvent qs qs Solvent

(A) Process for the Preparation of Polymer Matrix:

Polymer mixture: Polyethylene oxide and fast emerald green shade weremixed in water for at least 180 minutes at about 1400 rpm to about 2000rpm. Sucralose, hydroxypropyl cellulose (molecular weight 140K),hydroxypropyl cellulose, HPC-SSL (molecular weight 40K) andhydroxypropyl cellulose (molecular weight 370K) were added and mixed forat least 120 minutes at about 1600 rpm to 2000 rpm. Peppermint Oil wasadded to water and the resultant dispersion was then added to thepolymer mixture and mixed for at least 30 minutes. The resultant mixturewas further mixed under vacuum (248 torr) for at least for 30 minutes ata speed of 350 rpm and at temperature of 22.9° C.

Coating station: A roll was placed on an unwind stand and the leadingedge was thread through guide bars and coating bars. The silicone-coatedside of the liner was placed faced up. A gap of 40 millimeters wasmaintained between the coating bars. The oven set point was adjusted to70° C. and the final drying temperature was adjusted to 85° C.

Coating/drying process: The polymer mixture was poured onto the linerbetween the guide bars and the coating bars. The liner was pulled slowlythrough the coating bar at a constant speed by hand until no liquid wasremained on the coating bars. The liner was cut to approximately 12-inchlength hand sheets using a safety knife. Each hand sheet was placed on adrying board and was tapped on the corners to prevent curl duringdrying. The hand sheets were dried in the oven until the moisturecontent was less than 5% (approximately 30 minutes) and then removedfrom the drying board. The coating weights were checked against theacceptance criteria, and if met, the hand sheets were then stacked andplaced in a 34 inch×40 inch foil bag that was lined with PET releaseliner.

(B) Process for the Preparation of Deposition Solution:

FDC blue was dissolved in ethyl alcohol for at least 180 minutes.Dexmedetomidine hydrochloride was added to the ethyl alcohol solutionwith continuous stirring for 10 minutes at about 400 rpm to about 800rpm. Hydroxypropyl cellulose (40K) and hydroxypropyl cellulose (140K)were added to the mixture, and stirred for at least 30 minutes until allthe materials were dissolved.

(C) Process for the Preparation of Micro-Deposited Matrix:

The deposition solution obtained in Step (B) above was filled into apipette to the required volume (determined according to the specificdrug product strength of the final product). An appropriate amount (1.5microliters=approximately 5 μg) of the deposition solution weredeposited (e.g. as droplets) onto the polymer matrix obtained in Step(A), and repeated to a total of 10 times (i.e. 10 deposits/droplets)with space between each deposit to prevent merging of thedeposits/droplets and allow subsequent cutting of the film intoindividual drug-containing units. The film was initially die cut inindividual units with dimensions of 22 mm×8.8 mm containing a singledeposit of the drug-containing composition. The die cut micro-depositedmatrixes were then dried in an oven for 70° C. for 10 minutes andfurther die cut into 10 units with each unit containing a single depositof the drug-containing composition.

(D) Packaging:

Each defect-free unit was sealed individually into a foil pouch, whichwas then heat sealed. If the heat seal was acceptable the package wasconsidered as an acceptable unit for commercial use.

Other unit strengths (e.g. 40 μg and 60 μg films) were similarlyprepared by varying the concentrations of drug, polymers and colorantwithin the drug-containing composition. For example, the 40 μg and 60μg, films were prepared from drug-containing compositions containing,respectively, approximately 2× and 3×, the amounts of drug, polymers andcolorant that appear in the 20 μg drug-containing composition describedin table 6 above.

EXAMPLE 2

TABLE 7 Dexmedetomidine deposited on the surface of a polymer matrixfilm composition Concentration Concentration Concentration mg/unitmg/unit mg/unit (80 μg (120 μg (180 μg Ingredients film) film) film)Function Drug-containing composition Dexmedetomidine 0.0945 0.142 0.213Active agent hydrochloride Hydroxypropyl 0.0812 0.122 0.183 Film formercellulose, HPC-SSL (MW = 40,000) Hydroxypropyl cellulose 0.0812 0.1220.183 Film former (MW = 140,000) FD&C Blue #1 Granular 0.0008 0.0010.002 Color Ethyl Alcohol as a q.s q.s. q.s. Solvent solvent Polymermatrix composition Hydroxypropyl cellulose 0.627 0.627 0.627 Film former(MW = 140,000) Hydroxypropyl 0.627 0.627 0.627 Film former cellulose,HPC-SSL (MW = 40,000) Hydroxypropyl cellulose 3.763 3.763 3.763 Filmformer (MW = 370,000) Fast Emerald Green 0.017 0.017 0.017 Color Shade(NO. 06507) Sucralose, USP-NF 0.130 0.130 0.130 Sweetener GradePeppermint Oil, NF 0.275 0.275 0.275 Flavor Polyethylene oxide 7.5267.526 7.526 Film former & (Sentry Polyox WSR Mucoadhesive 205 LEO NF)(MW = 600,000) Water as a solvent qs qs qs Solvent

The formulations (80 μg, 120 μg and 180 μg) in table7 were preparedusing the same manufacturing process as described above in Example 1.

EXAMPLE 3: A PHASE IB MULTICENTER, RANDOMIZED, DOUBLE-BLIND,PLACEBO-CONTROLLED, MULTIPLE ASCENDING DOSE STUDY TO DETERMINE EFFICACY,PHARMACOKINETICS AND SAFETY OF DEXMEDETOMIDINE HYDROCHLORIDE SUBLINGUALFILM IN TREATING AGITATION ASSOCIATED WITH SCHIZOPHRENIA

Primary Objective:

To determine the doses of dexmedetomidine hydrochloride sublingual filmneeded to effectively reduce symptoms of acute agitation associated withschizophrenia, schizoaffective disorder or schizophreniform disorderassessed using the Positive and Negative Syndrome Scale—ExcitedComponent (PEC) change from baseline after drug treatment.

Secondary Objective:

Determine PK, safety and tolerability of the various film strengths ofdexmedetomidine hydrochloride sublingual film in patients with acuteagitation associated with schizophrenia, schizoaffective disorder orschizophreniform disorder.

-   -   1. Describe overall clinical improvement after drug        administration by Clinical Global Impression—Improvement scale        (CGI-I).    -   2. Describe the duration of calming effect as measured by PEC        and ACES.    -   3. Determine the safety profile of dexmedetomidine hydrochloride        sublingual film as measured by vital signs and reports of        adverse events.    -   4. Describe the overall tolerability in terms of adverse event        reports and local site (oral/sublingual) tolerability of the        sublingual film.    -   5. Describe the pharmacokinetics of dexmedetomidine        hydrochloride sublingual film in the patient population.    -   6. Visual Analog Scales (VAS) to capture subject's opinion on        taste and acceptability as well as questions regarding        likability of study medication.

Methodology: This was a two-stage adaptive Phase Ib trial design. It wasa randomized, double-blind, placebo-controlled, multiple ascending dosestudy assessing efficacy, pharmacokinetics, safety and tolerability ofdexmedetomidine hydrochloride sublingual film dosing in adult (18-65years old) males and females with acute agitation associated withschizophrenia, schizoaffective disorder, or schizophreniform disorder.

The first stage was designed to characterize a safe and tolerable doserange which produced a calming effect as measured using the PEC totalscore. The second stage was designed to enroll a total of 40 subjectsper dose group in a three-arm placebo-controlled design to bettercharacterize the broader range of safety and tolerability as well asbetter estimate variability (effect size).

Adaptive evaluation of escalating dose regimens of 20 μg, 60 μg and 120μg were performed for the first stage, with an option to test adifferent dose should a safety or tolerability signal be observed. Maleand female adults with acute agitation associated with schizophrenia,schizoaffective disorder, or schizophreniform disorder were enrolled ineach cohort. Investigators were permitted to repeat dosing 1 hour afteradministration if there was a lack of significant efficacy (PEC changefrom baseline ≤40%) (maximum number of doses per subject was 2) and inthe absence of safety concerns.

Blinded periodic safety data reviews were undertaken after completion ofdosing each cohort to review all safety data as it became available.Dose escalation was allowed unless a safety or tolerability issue becameevident upon periodic regular safety reviews. Based upon blindedanalyses of the safety and tolerability of all subject cohorts,additional doses were selected.

Eligible subjects (acutely agitated subjects with schizophrenia,schizoaffective, or schizophreniform disorder) were identified inoutpatient clinics, mental health, psychiatric or medical emergencyservices including medical/psychiatric observation units, or as newlyadmitted to a hospital setting for acute agitation or already inhospital for chronic underlying conditions. Subjects were domiciled in aclinical research setting or hospitalized to remain under medicalsupervision while undergoing screening procedures to assess eligibility.

Upon confirmation of eligibility, subjects were randomized todexmedetomidine hydrochloride sublingual film or placebo film. At thebeginning of each study session, a single dose of dexmedetomidinehydrochloride sublingual film was self-administered sublingually, aftertraining with a placebo film and under the supervision of an unblindedstaff who did not participate in evaluation of safety or efficacy. Thedrug film was retained in the sublingual (SL) cavity until dissolved.Participants were also evaluated for local irritation around the areawhere the film was placed. Efficacy and safety assessments wereconducted periodically before and after dosing. If reduction in PEC wasless than or equal to 40% one hour after the first administration, theinvestigator could administer a second dose of dexmedetomidinehydrochloride sublingual film (of the same randomized dose) with anadditional PEC assessment completed at 1.5 hr post-dose. All effortswere made to have the patient perform all assessments as per protocol.However, should the patient's situation warrant it, standard of caretreatment was initiated, preferably after the 4 hr assessments werecompleted. In Stage 1 each cohort included 27 subjects randomized 2:1 todexmedetomidine hydrochloride sublingual film or placebo film (i.e. 18received dexmedetomidine hydrochloride sublingual film and 9 receivedplacebo film). Three doses were initially planned (total of 81subjects). Per protocol, different or additional doses could be testedbased on ongoing safety reviews, and two additional dose levels weretested: 80 μg and 180 (Table 8).

Efficacy Assessments:

The efficacy of dexmedetomidine hydrochloride sublingual film onreducing acute agitation was assessed using the Positive and NegativeSyndrome Scale—Excited Component (PEC) scale which was performed atscreening, baseline (i.e. also referred to as pre-dose) and at 10, 20,30, 45 min; 1, 1.5, 2, 4, 6 and 24 hours post the first dose.

-   -   Overall agitation and sedation were evaluated with the        Agitation-Calmness Evaluation Scale (ACES), which was performed        at baseline (pre-dose) and at 2 and 4 hours post-first dose.    -   The change in agitation in response to treatment was also        measured by the Clinical Global Impressions—Improvement (CGI-I),        performed at 1, 2 and 4 hours post the first dose.

Safety and Tolerability Assessments:

AEs, clinical laboratory tests, electrocardiogram (ECG) with rhythmstrip, and vital signs were monitored for tolerability assessment. Allobserved and volunteered AEs were recorded. The relationship of AEs tothe study drugs was graded as not related, unlikely/remotely related,possibly related, probably related or definitely related by theinvestigators.

Resting vital signs including systolic blood pressure (SBP), diastolicblood pressure (DBP), and heart rate, as well as ECG were measured atprior to the PK assessments. Resting vital signs (SBP, DBP and HR) weretaken at screening, baseline (pre-dose) and at 30 min, 1, 2, 4 and 8hours post-first dose. Orthostatic measurements which included (SBP,DBP, HR, respiratory rate and temperature) were taken at screening,pre-dose, 2, 4 and 24 hours post-first dose. ECGs were conducted atscreening, baseline (pre-dose), 2 and 24 hours post-first dose. Theapplication site of the SL preparation (buccal mucosa) were alsoinspected for any signs of local irritation.

Safety and tolerability assessments were continued until the morning ofDay 3 (day of discharge) and were repeated on Day 7(+2). AEs evaluationwere conducted at screening, baseline (pre-dose), 2 hours, Day 3 and Day7(+2) post-the first dose. Safety Labs including chemistry, hematology,urinalysis, UDS, alcohol breathalyzer, and urine pregnancy wereperformed at screening, Day 3 and Day 7(+2).

Any abnormal vital sign measurement, clinical laboratory test, physicalexamination finding, or ECG parameter deemed clinically significant bythe investigator was repeated, including test results obtained on thefinal study day or upon early termination. For any test abnormalitydeemed clinically significant, repeat analysis was performed during thefollow-up period and until the value returned to baseline (or withinnormal limits) or the investigator deemed the abnormality to be stableand no longer of clinical concern.

Three analysis populations were defined for the study:

-   -   Safety Population: All subjects who receive study drug    -   Intent to treat (ITT) Population: All subjects in the Safety        Population who have a PEC Score    -   Per Protocol (PP) Population: All subjects in the ITT Population        with no major protocol deviations

Subjects were on a range of typically prescribed antipsychotics.

TABLE 8 Arms and Interventions Anns Intervention Placebo Comparator:Placebo Drug: Placebo film Sublingual Film with no Placebo film fordexmedetomidine active drug; single hydrochloride administrationExperimental: 20 μg Drug: Sublingual film containing Sublingual Filmcontaining dexmedetomidine hydrochloride 20 μg dexmedetomidine;Administration: Sublingual film containing single administration withdexmedetomidine for the treatment of repeat dose after 1 hour agitationassociated with Schizophrenia Experimental: 60 μg Drug: Sublingual filmcontaining Sublingual Film containing dexmedetomidine hydrochloride. 60μg dexmedetomidine; Administration: Sublingual film containing singleadministration dexmedetomidine for the treatment of agitation associatedwith Schizophrenia Experimental: 80 μg Drug: Sublingual film containingSublingual Film containing dexmedetomidine hydrochloride. 80 μgdexmedetomidine; Administration: Sublingual film containing singleadministration dexmedetomidine for the treatment of agitation associatedwith Schizophrenia Experimental: 120 μg Drug: Sublingual film containing2 Sublingual Films, each dexmedetomidine hydrochloride. containing 60 μgAdministration: Sublingual film containing dexmedetomidine;dexmedetomidine for the treatment of single administration of 2agitation associated with Schizophrenia films Experimental: 180 μg Drug:Sublingual film containing 3 Sublingual Films, each dexmedetomidinehydrochloride. containing 60 μg Administration: Sublingual filmcontaining dexmedetomidine; dexmedetomidine for the treatment of singleadministration of 3 agitation associated with Schizophrenia films

Number of Subjects (Planned and Analyzed):

An estimated 81 subjects in Stage 1 were planned in 3 cohorts (27 percohort), however including the 2 additional cohorts (80 μg and 180 μgdexmedetomidine hydrochloride sublingual films), a total of 135 subjectswere enrolled in 5 cohorts and analyzed.

Diagnosis and Main Criteria for Eligibility:

Inclusion Criteria:

-   -   1. Male and female patients between the ages of 18 to 65 years,        inclusive.    -   2. Patients who had met Diagnostic and Statistical Manual of        Mental Disorders, Fifth Edition (DSM-5) criteria for        schizophrenia, schizoaffective, or schizophreniform disorder.    -   3. Patients who were judged to be clinically agitated at        screening and baseline (pre-dose with a total score of ≥14 on        the 5 items (poor impulse control, tension, hostility,        uncooperativeness, and excitement) comprising the PANSS Excited        Component (PEC).    -   4. Patients who have a score of ≥4 on at least 1 of the 5 items        on the PEC at baseline (pre-dose).    -   5. Patients who read, understood and provide written informed        consent.    -   6. Patients who were in good general health prior to study        participation as determined by a detailed medical history,        physical examination, 12-lead ECG with rhythm strip, blood        chemistry profile, hematology, urinalysis and in the opinion of        the Principal Investigator.    -   7. Female participants, if of child-bearing potential and        sexually active, and male participants, if sexually active with        a partner of child-bearing potential, who agreed to use a        medically acceptable and effective birth control method        throughout the study and for one week following the end of the        study. Medically acceptable methods of contraception that could        be used by the participant and/or his/her partner include        abstinence, birth control pills or patches, diaphragm with        spermicide, intrauterine device (IUD), condom with foam or        spermicide, vaginal spermicidal suppository, surgical        sterilization and progestin implant or injection. Prohibited        methods include: the rhythm method, withdrawal, condoms alone,        or diaphragm alone.

Exclusion Criteria:

-   -   1. Patients with agitation caused by acute intoxication,        including positive identification of alcohol by breathalyzer or        drugs of abuse or non-prescription drugs (with the exception of        tetrahydrocannabinol (THC)) during urine screening.    -   2. Patients treated within 4 hours prior to study drug        administration with benzodiazepines, other hypnotics or oral or        short-acting intramuscular antipsychotics.    -   3. Treatment with alpha-1 noradrenergic blockers (terazosin,        doxazosin, tamsulosin, and alfuzosin, and prazocin) or other        prohibited medications.    -   4. Patients with significant risk of suicide or homicide per the        investigator's assessment, or any suicidal behaviour in last 6        months prior to screening.    -   5. Female patients who had a positive pregnancy test at        screening or were breastfeeding.    -   6. Patients who had hydrocephalus, seizure disorder, or history        of significant head trauma, stroke, transient ischemic attack,        subarachnoid bleeding, brain tumor, encephalopathy, meningitis,        Parkinson's disease or focal neurological findings.    -   7. History of syncope or other syncopal attacks, current        evidence of hypovolemia, orthostatic hypotension, a screening        heart rate of <55 beats per minutes (bpm) or systolic blood        pressure (SBP)<110 mmHg or diastolic blood pressure (DBP)<70        mmHg.    -   8. Patients with laboratory or ECG abnormalities considered        clinically significant by the investigator or qualified designee        [Advanced heart block (second-degree or above atrioventricular        block without pacemaker), diagnosis of Sick sinus syndrome] that        would have clinical implications for the patient's participation        in the study.    -   9. Patients with serious or unstable medical illnesses. These        include current hepatic (moderate severe hepatic impairment),        renal, gastroenterologic, respiratory, cardiovascular (including        ischemic heart disease, congestive heart failure),        endocrinologic, or hematologic disease.    -   10. Patients who had received an investigational drug within 30        days prior to the current agitation episode.    -   11. Patients who were unable to use the sublingual film or        considered by the investigator, for any reason, to be an        unsuitable candidate for receiving dexmedetomidine; e.g.        patients with a history of allergic reactions to        dexmedetomidine.

Test Product, Dose and Mode of Administration:

Dexmedetomidine sublingual film (formulation of Examples 1 and 2 above)was tested in a small, solid-dose film formulations with dimensions ofapproximately 193.6 mm2 in area and 0.7 mm thick designed to completelydissolve in the SL space within 2-3 minutes. Reference therapy,

Dose and Mode of Administration:

Matching placebo films to be taken sublingually as described above.

Duration of Treatment: 1 day

Criteria for Evaluation: The primary endpoints in this study pertainedto the efficacy, pharmacokinetics, safety, and tolerability of each doselevel.

Efficacy: The efficacy of dexmedetomidine hydrochloride sublingual filmon acute agitation was assessed using the Positive and Negative SyndromeScale—Excited Component (PEC) scale. PEC comprised 5 items associatedwith agitation: poor impulse control, tension, hostility,uncooperativeness, and excitement; each scored 1 (minimum) to 7(maximum). The PEC, the sum of these 5 subscales, thus ranging from 5 to35.

Overall agitation and sedation were evaluated with theAgitation-Calmness Evaluation Scale (ACES), where 1 indicates markedagitation; 2—moderate agitation; 3—mild agitation; 4—normal behavior;5—mild calmness; 6—moderate calmness; 7—marked calmness; 8—deep sleep;and 9—unarousable.

The change in agitation in response to treatment was also measured bythe Clinical Global Impressions—Improvement (CGI-I). CGI-I scores rangefrom 1 to 7:0=not assessed (missing), 1=very much improved, 2=muchimproved, 3=minimally improved, 4=no change, 5=minimally worse, 6=muchworse, 7=very much worse.

Pharmacokinetics:

Pharmacokinetic analysis was performed using dexmedetomidine plasmaconcentrations after administration of dexmedetomidine hydrochloridesublingual films. A dose proportionality analysis was conducted.

Safety and tolerability: AEs, clinical laboratory tests, ECG with rhythmstrip, vital signs and signs of local irritation (buccal) were monitoredfor safety and tolerability.

Additional Assessments:

-   -   Demographic Data    -   Medical History    -   Prior and Concomitant Medication    -   Physical Examination and    -   Pregnancy testing

Statistical Analysis:

Efficacy Analyses: The primary efficacy endpoint of the study was theabsolute change from baseline in PEC score at 120 mins (2 hours). Theintent to treat population (ITT) was analyzed and consisted of allpatients who took any study medication and who had both baseline and atleast 1 efficacy assessment after dosing. Analyses were conducted usinga restricted maximum likelihood repeated measures mixed model on changefrom baseline values with baseline as a covariate and timepoint, and itsinteraction with treatment groups as repeated measures using anunstructured covariance structure. Responder comparisons were made viaFisher's exact test.

Pharmacokinetic Analyses:

Pharmacokinetic analysis was conducted using a validated install ofPhoenix® WinNonlin® version 8.1. Non-compartmental analysis was alsoconducted on the final audited data which consisted of a total of 135participants in 5 cohorts receiving 20, 60, 80 (1×20 μg films and 1×60μg films), 120 (2×60 μg films) and 180 μg (3×60 μg films) ofdexmedetomidine sublingual films. All areas under the concentration-timecurve (AUCs) were calculated using the linear trapezoidal method. Doseproportionality was assessed using a power model for PK parameters. Meanand individual concentration (sorted by dose level) versus time plotswere generated.

Safety and Tolerability Analyses:

Safety data analysis was conducted on all subjects receiving at least 1dose of study drug. The number and percentage of subjects experiencing 1or more AEs were summarized by treatment, relationship to study drug,and severity. AEs were coded using Medical Dictionary for RegulatoryActivities (Med DRA) terminology. Listings of subjects who experiencewithdrawal due to an AE, serious AEs and/or death were presented.Laboratory parameters were summarized by treatment using descriptivestatistics and data listings of clinically significant abnormalities.Vital signs and ECG data were summarized by changes from baseline valuesat each dose level using descriptive statistics.

Sample Size Determination: The sample size is based on clinicalexperience and judgment relative to the study design and objectives inStage 1. A sample size of at least 18 subjects on active drug in eachdosing cohort should provide adequate clinical information to meet theobjectives of the study.

All efficacy, safety, and tolerability measurements were conducted atregularly scheduled intervals as described in table 9.

TABLE 9 Schedule of Events Treatment Evaluation Day 1 ScreeningPre-Dose¹ Post Dose Time¹ Time point Pre- −1 hr to 10 20 30 45 1 1.5 2 46 8 Activity treatment time 0 min min min min hr hr hr hr hr hr InformedConsent X Medical History X Demographics X Weight X Height X BMI X MINIX PANSS¹⁰ X X Physical Exam X Safety Labs⁵ X ECG with rhythm strip ⁹ X XX Resting vital signs² X X X X X X X X Orthostatic vital signs² X X X XX Admit to Unit X Training/Review of X study drug administrationInclusion/Exclusion X X criteria Randomization X Study drug Xadministration⁸ PCRS¹¹ X X X PEC³ X X X X X X X X X X X ACES X X XCGI-Severity⁴ X X CGI-Improvement⁴ X X X X C-SSRS X Buccal (SL)assessment X X X for local irritation⁷ Visual Analog Scales X LikabilityQuestion X PK Sampling⁶ X X X  X* X X X Concomitant X X MedicationsAdverse Events X X X X X X X X X X X X Treatment Evaluation Day 2, 3 and7 Day 2 Follow-Up Day 3 Screening (+1) Discharge Day 7 (+2) Time point24 hr End of Activity Pre-treatment (−9/+12 hr) Study Informed Consent XMedical History X Demographics X Weight X X Height X BMI X MINI XPANSS¹⁰ X Physical Exam X X Safety Labs⁵ X X X ECG with rhythm strip ⁹ XX Resting vital signs² X X Orthostatic vital signs² X X Admit to Unit XTraining/Review of study drug administration Inclusion/Exclusion Xcriteria Randomization Study drug administration⁸ PCRS¹¹ X X PEC³ X XACES CGI-Severity⁴ X CGI-Improvement⁴ C-SSRS X X Buccal (SL) assessmentX for local irritation⁷ Visual Analog Scales Likability Question PKSampling⁶ X Concomitant X X X X Medications Adverse Events X X X XAbbreviations: ACES = Agitation-Calmness Evaluation Scale; BMI = bodymass index; CLIA = Clinical Laboratory Improvement Amendments; CGI-I =Clinical Global Impression-Improvement; CGI-S = Clinical GlobalImpression-Severity; C-SSRS = Columbia-Suicide Severity Rating Scale;DBP = diastolic blood pressure; ECG = electrocardiogram; MINI = MiniInternational Neuropsychiatric Interview; PANSS = Positive and NegativeSyndrome Scale; PCRS = Placebo Control Reminder Script; PEC = Positiveand Negative Syndrome Scale—Excited Component; PK = pharmacokinetic; SBP= systolic blood pressure; SL = sublingual; UDS = urine drug screenNotes to the Schedule of Events: ¹Pre-dose assessments had a window of60 minutes prior to first dose. Timing of all subsequent assessments wasrelative to the first dose. All post-dose assessments had a window of ±3minutes until 2 hours and ±10 minutes until 8 hours. ²Resting vitalsigns (SBP, DBP and HR) will be taken at Screening, Pre-dose and at 30min, 1, 2, 4 and 8 hours post first dose. Triplicate measurements wereperformed in case of Systolic BP <90 mmHg, Diastolic BP <60 mmHg orPulse <60 bpm. Orthostatic measurements (SBP, DBP, HR, respiratory rateand temperature) were taken at Screening, Pre-dose, 2, 4 and 24 hourspost first dose. Vital signs were done prior to each PK sample. ³PEC wasperformed at Screening, Pre-dose and at 10, 20, 30, 45 min; 1, 1.5, 2,4, 6 and 24 hours post first dose. ⁴CGI-Severity was performed atScreening and pre-dose. CGI-Improvement was performed at 1, 2 and 4hours post first dose. The PEC (preceded by the Placebo Control ReminderScript [PCRS], when required) was done prior to any other assessments.⁵Safely Labs included chemistry, hematology, urinalysis, UDS (locallab)(only conducted at screening), alcohol breathalyzer (only conductedat screening), and urine pregnancy (only conducted at screening).Screening/enrollment labs: local labs drawn within 7 days prior toscreening may suffice with the exception of urine drug screen. Ifresults not available on the same day, a ‘desktop’ or non-CLIA testmight be performed; to confirmed, results from a CLIA-certifiedlaboratory should be recorded once available. ⁶PK blood samples werecollected Predose (up to 15 min prior to first and, if applicable,second dose), 1, 1.5, 2, 4, 6, 8-10 hrs (collect one sample between 8and 10 hours) and 24 hr after first dose. A sample may not be collectedif the Physician indicates in source documents that the patient is in amental stale that was not conducive to PK sample collection.Non-compliance or refusal of all or any PK draw were exclusionary norresult in ET. All PK collections had a window of ±3 minutes with theexception of the 24 hour post-dose collection which had a window of ±1hour. *For re-dosed subjects only: PK blood sample was collected at 2.5hrs post first dose in addition to the other times. ⁷Buccal exam (at 30min ± 15, and other times ±30 min) for local irritation performed byblinded staff. Day 2 follow up with +1 day window. ⁸In theinvestigator’s clinical judgement the same randomized dose might berepeated at 1 hr if there was no clinical effect (PEC change frombaseline ≤40%) and in the absence of safety concerns. ⁹ ECG for pre-dosewas not repeated if screening ECG was conducted on the day of dosing.ECGs collected following treatment were performed prior to PKassessments ¹⁰PANSS had administered at any time on the day of dosingprior to dosing and post-dose. Full PANSS was to be conducted inaddition to stand alone PEC. ¹¹PCRS was performed immediately prior tothe PEC

Results Summary:

1. Data Sets Analyzed

The number of subjects in each dataset were the same for all 3populations (ie, Safety, ITT and PP) (Table 10). Additionally, thenumber of subjects in each dataset were the same for the pharmacokineticpopulation, as all subjects provided blood samples for analysis.

TABLE 10 Summary of Datasets Analyzed Dexmedetomidine sublingual filmPlacebo 20 μg 60 μg 80 μg 120 μg 180 μg Overall Dataset (N = 45) (N =18) (N = 18) (N = 18) (N = 48) (N = 18) (N = 135) Safety Population 45(100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 135(100.0) Intent-to-Treat Population 45 (100.0) 18 (100.0) 18 (100.0) 18(100.0) 18 (100.0) 18 (100.0) 135 (100.0) Per-Protocol Population 45(100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 135(100.0)

Disposition:

A total of 135 subjects were enrolled and received study drug andcomprised the Safety Population. Of the 135 subjects, all subjectscompleted the inpatient study drug treatment period; 127 subjectscompleted the end of the study period (i.e. study Day 7). Of the 8subjects who did not complete the study, 7 subjects were lost tofollow-up after discharge from the inpatient facility on study Day 3 and1 subject withdrew from the study on study Day 3.

2. Demographics and Baseline Characteristics:

For subjects in the Safety Population (N=135), mean age was 47.6 years,the majority of subjects were male (65.9% [89/135]), and mean BMI was30.58 kg/m2. Subjects were predominantly Black or African American(74.8% [101/135]) and not Hispanic or Latino (90.4% [122/135]). Themajority of subjects in all treatment groups had a diagnosis ofschizophrenia (assessed by the Mini-International NeuropsychiatricInterview [MINI-Plus] instrument). The proportion of subjects withschizophrenia ranged from 72.2% to 83.3% in the Dexmedetomidinesublingual film treatment groups. Based on MINI-Plus results, allsubjects in the study met the inclusion criteria of having a diagnosisof schizophrenia, schizoaffective, or schizophreniform disorder (Table11).

TABLE 11 Demographics and Baseline Characteristics Dexmedetomidinesublingual film Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Overall Variable(N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) (N = 135) Age(years) Mean (SD) 48.4 (10.88)  50.1 (7.37)   45.8 (10.87)  50.2 (9.72) 40.5 (8.40)  49.1 (10.61)  47.6 (10.26)  Median 52.0  50.0  47.0  52.0 40.0  48.0  50.0  Min-Max 21, 63 29, 59 26, 63 26, 63 25, 54 26, 64 21,64 Gender, n % Male 27 (60.0) 9 (50.0) 15 (83.3) 13 (72.2) 13 (72.2) 12(66.7) 89 (65.9) Female 18 (40.0) 9 (50.0)  3 (16.7)  5 (27.8)  5 (27.8) 6 (33.3) 46 (34.1) Race, n % Black or 37 (82.2) 13 (72.2)  11 (61.1) 12(66.7) 15 (83.3) 13 (72.2) 101 (74.8)  African American White  7 (15.6)5 (27.8)  7 (38.9)  6 (33.3)  2 (11.1)  4 (22.2) 31 (23.0) Asian 0   0  0   0   0   1 (5.6) 1 (0.7) Multiple 1 (2.2) 0   0   0   0   0   1 (0.7)Unknown 0   0   0   0   1 (5.6) 0   1 (0.7) Ethnicity, n % Not Hispanic44 (97.8) 16 (88.9)  15 (83.3) 15 (83.3) 16 (88.9) 16 (88.9) 122 (90.4) or Latino Hispanic or 1 (2.2) 2 (11.1)  3 (16.7)  3 (16.7)  2 (11.1)  2(11.1) 13 (9.6)  Latino Height (cm) Mean (SD) 171.15 (10.25)   169.29(10.63)    174.08 (11.12)   174.90 (10.66)   175.33 (13.81)   174.87(8.95)    172.85 (10.87)   Median 169.00  170.30  174.05  175.90 175.70  175.25  173.00  Min-Max 149.9, 198.1 149.9, 188.0 150.5, 195.0157.0, 198.1 137.0, 205.0 160.0, 188.4 137.0, 205.0 Weight (kg) Mean(SD) 86.86 (16.62)  86.92 (18.83)   94.89 (15.53)  92.84 (19.77)  90.54(18.04)  100.53 (19.10)   91.05 (18.06)  Median 84.10 82.50 97.10 91.9590.80 100.45  91.00 Min-Max  56.8, 121.2  58.9, 119.6  64.9, 127.7 65.3, 133.6  57.2, 135.4  68.4, 143.2  56.8, 143.2 Body Mass Index(kg/m²) Mean (SD) 29.74 (5.61)   30.23 (5.37)    31.45 (5.47)   30.56(7.02)   29.81 (6.96)   32.97 (6.47)   30.58 (6.06)   Median 29.27 29.5831.09 30.03 29.08 32.56 29.40 Min-Max 17.9, 41.5 20.9, 40.3 22.5, 42.820.9, 44.5 18.3, 45.4 24.8, 45.4 17.9, 45.4 Abbreviations: cm =centimeter, kg = kilogram; max = maximum; min = minimum; SD = standarddeviation; Percentages are based on the number of Safety Populationsubjects in each treatment arm.

3. Efficacy

Dexmedetomidine sublingual film significantly improved the severity ofagitation from baseline as measured by PEC, ACES scales and CGI-Iscores. Key efficacy findings at 2 hours post-dose are presented below.

(a) Primary Efficacy Endpoint (PEC reduction): a reduction in the PECscore (PANSS or the Positive and Negative Syndrome Scale, ExcitatoryComponent) for agitation was observed with rapid calming withoutexcessive sedation at the clinical regulatory endpoint and at earliertime-points. The primary efficacy endpoint was the mean change frombaseline in PEC total score at 2 hours (120 minutes) compared toplacebo. There were 5 dose cohorts (20 μg, 60 μg, 80 μg, 120 μg and 180μg) with 18 active patients (total of 90 patients) and 9 placebopatients (total of 45 patients) in each cohort. Active patients in eachof the 5 dose cohorts were compared to placebo patients from all 5cohorts (pooled placebo group). The change from baseline in PEC at 2hours for patients treated with dexmedetomidine sublingual film wascompared with placebo using a mixed model repeated measures (MMRM)analysis, with baseline PEC, treatment group, time, the interactionbetween treatment groups and time, and the interaction between baselinePEC and time as covariates.

The efficacy of dexmedetomidine hydrochloride sublingual film asmeasured by PEC reduction is dose-responsive and robust. The decreasefrom baseline in PEC score in the 180 μg dose group showed significantresponse with a −10.8 mean change from baseline (CFB) total PEC score at2 hours post dosing compared to placebo (Table 12 and FIG. 1 ). Meanchanges from baseline were −9.2 and −7.3 points, respectively for the120 μg and 80 μg treatment groups, compared to placebo (−4.5 Meanchange). LSM mean differences from placebo were −2.9 (P=0.0210), −4.6(P=0.0003), and −6.3 (P<0.0001) for the 80 μg, 120 μg, and 180 μgtreatment groups (table 11) Mean changes from baseline at 2 hours postdosing in the 20 μg and 60 μg groups were not significantly differentthan placebo. Additionally, as early onset of action is an importantattribute for therapy in reducing agitation, the 180 μg group showed astatistically significant separation from placebo as early as 45 minutespost dosing (LS mean difference of −3.5 [P<0.0049]).

TABLE 12 Summary of Change from Baseline at all Timepoints in PANSS-PECTotal Score by Treatment Group (Intent to treat population)Dexmedetomidine Sublingual film Time Point Placebo 20 μg 60 μg 80 μg 120μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N =18) Baseline, n Mean (SD) 18.1 (2.37)  17.5 (2.33)  17.5 (2.07)  17.4(1.42)  18.3 (1.64)  18.3 (2.95) 10 minutes post-dose Mean (SD) 16.0(4.33)  16.2 (2.86)  15.1 (3.92)  15.2 (3.26)  17.8 (3.19)  16.8 (4.26)Change from baseline, mean (SD) −2.1 (3.60)  −1.3 (1.67)  −2.4 (3.45) −2.2 (3.01)  −0.6 (2.31)  −1.5 (2.68) Change from baseline, LS mean(SE) −2.1 (0.5)  −1.4 (0.7) −2.5 (0.7) −2.3 (0.7) −0.5 (0.7) −1.4 (0.7)LSM difference (SE)^(a)  0.7 (0.9) −0.4 (0.9) −0.2 (0.9)  1.6 (0.9)  0.7(0.9) 20 minutes post-dose Mean (SD) 15.2 (4.41)  15.1 (2.88)  14.1(4.64)  14.2 (3.81)  15.8 (3.47)  15.6 (4.12) Change from baseline, mean(SD) −2.9 (3.60)  −2.4 (2.33)  −3.4 (4.29)  −3.2 (3.89)  −2.5 (3.03) −2.7 (2.72) Change from baseline, LS mean (SE) −2.9 (0.5)  −2.5 (0.8)−3.5 (0.8) −3.3 (0.8) −2.4 (0.8) −2.6 (0.8) LSM difference (SE)^(a)  0.4(1.0) −0.6 (1.0) −0.4 (1.0)  0.5 (1.0)  0.2 (1.0) 30 minutes post-doseMean (SD) 14.8 (4.94)  14.2 (2.79)  13.1 (4.97)  12.7 (3.82)  15.0(3.74)  14.2 (4.48) Change from baseline, mean (SD) −3.3 (4.46)  −3.3(3.07)  −4.4 (4.67)  −4.7 (3.82)  −3.3 (3.56)  −4.1 (3.26) Change frombaseline, LS mean (SE) −3.2 (0.6)  −3.4 (0.9) −4.5 (0.9) −4.8 (0.9) −3.2(0.9) −4.0 (0.9) LSM difference (SE)^(a) −0.2 (1.1) −1.2 (1.1) −1.5(1.1)  0.0 (1.1) −0.7 (1.1) 45 minutes post-dose Mean (SD) 14.5 (4.88) 13.8 (3.15)  12.4 (5.41)  11.3 (4.80)  13.3 (4.66)  11.1 (5.08) Changefrom baseline, mean (SD) −3.6 (4.14)  −3.7 (2.83)  −5.1 (5.11)  −6.1(5.13)  −5.1 (4.92)  −7.2 (4.73) Change from baseline, LS mean (SE) −3.6(0.7)  −3.8 (1.0) −5.2 (1.0) −6.2 (1.0) −5.0 (1.0) −7.1 (1.0) LSMdifference (SE)^(a) −0.2 (1.2) −1.6 (1.2) −2.6 (1.2) −1.4 (1.2) −3.5(1.2) 1 hour post-dose Mean (SD) 14.0 (4.65)  13.0 (4.33)  11.4 (5.40) 10.9 (5.03)  10.9 (5.29)  9.2 (4.08) Change from baseline, mean (SD)−4.1 (4.29)  −4.5 (3.67)  −6.1 (5.49)  −6.5 (5.28)  −7.4 (5.48)  −9.1(4.58) Change from baseline, LS mean (SE) −4.0, 0.7 −4.6 (1.1) −6.2(1.1) −6.6 (1.1) −7.3 (1.1) −9.0 (1.1) LSM difference (SE)^(a) −0.6(1.3) −2.2 (1.3) −2.6 (1.3) −3.3 (1.3) −5.0 (1.3) P-value^(b) 0.66470.0968 0.0488 0.0130  0.0002 1.5 hours post-dose Mean (SD) 13.8 (4.62) 12.1 (4.13)  11.3 (5.26)  10.8 (5.81)  10.8 (5.52)  7.8 (3.05) Changefrom baseline, mean (SD) −4.3 (4.43)  −5.4 (3.96)  −6.2 (5.24)  −6.6(6.05)  −7.5 (5.57) −10.4 (4.38) Orange from baseline, LS mean (SE) −4.3(0.7)  −5.5 (1.1) −6.3 (1.1) −6.7 (1.1) −7.4 (1.1) −10.4 (1.1)  LSMdifference (SE)^(a) −1.2 (1.3) −2.0 (1.3) −2.4 (1.3) −3.1 (1.3) −6.1(1.3) P-value^(b) 0.3661 0.1279 0.0743 0.0199 <0.0001 2 hours post-doseMean (SD) 13.6 (4.56)  11.0 (3.87)  11.4 (5.07  10.1 (5.45)  9.1 (4.20) 7.4 (2.68) Change from baseline, mean (SD) −4.5 (4.58)  −6.5 (3.91) −6.1 (5.09)  −7.3 (5.70)  −9.2 (4.47) −10.8 (3.15) Orange frombaseline, LS mean (SE) −4.5 (0.7)  −6.6 (1.0) −6.1 (1.0) −7.4 (1.0) −9.1(1.0) −10.8 (1.0)  LSM difference (SE)^(a) −2.1 (1.2) −1.7 (1.2) −2.9(1.2) −4.6 (1.2) −6.3 (1.2) P-value^(b) 0.0933 0.1850 0.0210 0.0003<0.0001 4 hours post-dose Mean (SD) 13.7 (4.13)  9.4 (3.90)  11.2 (5.11) 10.2 (5.12)  9.1 (3.69)  7.3 (2.54) Change from baseline, mean (SD)−4.4 (4.44)  −8.1 (4.32)  −6.3 (5.22)  −7.2 (5.48)  −9.2 (4.02) −10.9(3.61) Orange from baseline, LS mean (SE) −4.3 (0.7)  −8.1 (1.0) −6.4(1.0) −7.3 (1.0) −9.1 (1.0) −10.9 (1.0)  LSM difference (SE)^(a) −3.8(1.2) −2.1 (1.2) −2.9 (1.2) −4.8 (1.2) −6.5 (1.2) P-value^(b) 0.00220.0895 0.0172 0.0001 <0.0001 6 hours post-dose Mean (SD) 13.1 (4.22) 10.0 (4.00)  11.9 (5.21)  10.1 (4.90)  9.3 (4.23)  7.2. (2.51) Changefrom baseline, mean (SD) −5.0 (4.79)  −7.5 (4.03)  −5.6 (5.19)  −7.3(5.30)  −9.1 (5.00) −11.1 (3.47) Change from baseline, LS mean (SE) −4.9(0.7)  −7.6 (1.1) −5.6 (1.1) −7.4 (1.1) −9.0 (1.1) −11.0 (1.1)  LSMdifference (SE)^(a) −2.7 (1.3) −0.7 (1.3) −2.5 (1.3) −4.0 (1.3) −6.0(1.3) P-value^(b) 0.0375 0.5752 0.0490 0.0018 <0.0001 24 hours post-doseMean (SD) 13.5 (3.91)  11.4 (3.58)  13.6 (4.10)  11.3 (4.18)  12.8(3.59)  9.4 (4.82) Change from baseline, mean (SD) −4.6 (4.03)  −6.1(4.23)  −3.9 (4.34)  −6.1 (4.50)  −5.6 (3.29)  −8.9 (3.53) Change frombaseline, LS mean (SE) −4.6 (0.6)  −6.2 (0.9) −4.0 (0.9) −6.2 (0.9) −5.5(0.9) −8.8 (0.9) LSM difference (SE)^(a) −1.6 (1.1)  0.6 (1.1) −1.6(1.1) −0.9 (1.1) −4.2 (1.1) P-value^(b) 0.1464 0.5697 0.1407 0.4310 0.0002 Note: subjects counts for all timepoints were 18 subjects foreach dexmedetomidine sublingual film treatment group and 45 subjects forthe placebo group ^(a)Treatment effect between dexmedetomidinesublingual film and placebo ^(b)p value comparing dexmedetomidinesublingual film and placebo

PEC Responder Analyses: The proportion of treatment responders, definedas those with a 40% decrease from baseline in PEC total score at 2 hourspost dose, was greatest in the 180 group (94.4% [P<0.0001] for 180 μg,68.8% [P=0.0158] for 120 μg, 58.8% for 80 μg [P=0.0759]) andsignificantly greater than placebo (31% responders) (Table 13 and FIG. 2). Response rates with 180 μg were significantly higher than placebostarting at 45 minutes post dose (44.4% versus 16.7%, respectively),continued to increase after 2 hours (to 94.4% at 4 and 6 hours) andsustained until at least 24 hours post-dose (83.3% versus 17.5%,respectively). Finally, the durability of calming effects of the 180 μgdose was remarkably prolonged with a sustained statistically significantreduction in PEC evident after 24 hrs. After a single dose in the 180group, 83.3% of subjects maintained response after 24 hours with a meanPEC decrease of −8.9 (Mean CFB) compared to 37.5% in the 120 μg group(−5.6 Mean CFB) and 43.8% in the 80 group (−6.1 Mean CFB. Response ratesover time for the 80 μg and 120 μg groups were high and similar betweenthe 2 groups (Table 13 and FIG. 2 ).

TABLE 13 Percent of Responders in the PEC Score (Intent to treatPopulation) Dexmedetomidine Sublingual Film Time Point Placebo 20 μg 60μg 80 μg 120 μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N-18) (N =18) (N = 18) 10 minutes post-dose Percent responders 11.9%   0% 12.5%5.9% 6.3% 5.6% 20 minutes post-dose Percent responders 14.3%   0% 25.0%23.5% 6.3% 5.6% 30 minutes post-dose Percent responders 21.4% 11.8%37.5% 23.5% 12.5% 11.1% 45 minutes post-dose Percent responders 16.7%17.6% 37.5% 41.2% 25.0% 44.4% 1 hour post-dose Percent responders 21.4%29.4% 43.8% 58.8% 56.3% 55.6% P-value^(a) 0.5178 0.1091 0.0120 0.02360.0150 1.5 hours post-dose Percent responders 26.2% 41.2% 56.3% 52.9%50.0% 77.8% P-value^(a) 0.3505 0.0612 0.0699 0.1190 0.0004 2 hourspost-dose Percent responders 31.0% 58.8% 43.8% 58.8% 68.8% 94.4%P-value^(a) 0.0759 0.3735 0.0759 0.0158 <0.0001 4 hours post-dosePercent responders 21.4% 64.7% 50.0% 64.7% 68.8% 94.4% P-value^(a)0.0024 0.0519 0.0024 0.0015 <0.0001 6 hours post-dose Percent responders28.6% 64.7% 43.8% 58.8% 68.8% 94.4% P-value^(a) 0.0173 0.3510 0.03990.0075 <0.0001 24 hours post-dose Percent responders 17.5% 43.8% 26.7%43.8% 37.5% 83.3% P-value^(a) 0.0838 0.4676 0.0838 0.1610 <0.0001 Aresponder is defined as a subject who achieved a ≥40% decrease frombaseline in PEC score after dosing. The number of subjects withnon-missing data in the dexmedetomidine sublingual film treatment groupswere: 18 (180 μg), 17 (20 μg and 80 μg), and 16 (60 μg and 120 μg); 42subjects in the placebo group had non-missing data. ^(a)P-value based ona comparison of dexmedetomidine sublingual film versus placebo via aFisher’s exact test

PANSS-EC (5 Items Subscale Scores): The PEC 5 subscale scores associatedwith agitation (ie, poor impulse control, tension, hostility,uncooperativeness, and excitement) were summarized in table 14, at 2hours post dosing, significant improvements (ie, decreases) frombaseline in all 5 PEC subscale scores were observed in the 80 μg, 120 μgand 180 μg groups compared to placebo; with the exception of“excitement” in the 80 μg group.

TABLE 14 Change from Baseline in PANSS-EC subscale scores at 2 hourspost dosing in schizophrenia patients (Intent to treat Population)Dexmedetomidine Sublingual Film PANNS-EC Subscale Placebo 20 μg 60 μg 80μg 120 μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N = 18) (N = 18)(N = 18) Poor impulse Control Baseline, Mean (SD) 3.5 (0.63)  3.5 (0.62) 3.5 (0.62)  3.3 (0.49)  3.4 (0.50)  3.4 (0.70) 2 hours post-dose Mean(SD) 2.7 (0.87)  2.1 (1.13)    2.2 (1.1.1)  1.9 (1.06)  1.7 (0.75)  1.4(0.70) Change from baseline, mean (SD) −0.8 (0.89)   −1.4 (1.14)  −1.3(1.13)  −1.4 (1.04)  −1.7 (1.03)  −2.0 (0.91) Change from baseline, LSmean (SE) −0.8 (0.1)  −1.4 (0.2) −1.3 (0.2) −1.4 (0.2) −1.7 (0.2) −2.0(0.2) LSM difference (SE)^(a) −0.6 (0.3) −0.5 (0.3) −0.6 (0.3) −0.9(0.3) −1.2 (0.3) p value 0.0307 0.0810 0.0178 0.0009 <0.0001 TensionBaseline, Mean (SD) 4.0 (0.64)  3.8 (0.65)  3.6 (0.92)  3.8 (0.71)  4.1(0.47)  4.1 (0.87) 2 hours post-dose Mean (SD) 3.0 (1.13)  2.4 (1.15) 2.3 (1.32)  2.1 (1.23)  1.9 (1.06)  1.5 (0.71) Change from baseline,mean (SD) −1.0 (1.24)   −1.3 (1.14)  −1.3 (1.19)  −1.7 (1.45)  −2.2(0.92)  −2.6 (1.04) Change from baseline, LS mean (SE) −0.9 (0.2)  −0.5(0.3) −0.5 (0.3) −0.8 (0.3) −1.2 (0.3) −1.6 (0.3) LSM difference (SE)a−0.5 (0.3) −0.5 (0.3) −0.8 (0.3) −1.2 (0.3) −1.6 (0.3) p value 0.13970.0947 0.0085 0.0002 <0.0001 Hostility Baseline, Mean (SD) 3.5 (0.73) 3.5 (0.62)  3.6 (0.70)  3.3 (0.77)  .3.6 (0.62)  3.6 (0.61) 2 hourspost-dose Mean (SD) 2.6 (1.12)  2.2 (0.71)  2.4 (1.04)  1.9 (1.11)  1.8(0.79)  1.4 (0.51) Change from baseline, mean (SD) −0.9 (1.11)   −1.3(0.84)  −1.2 (1.15)  −1.4 (1.14)  −1.7 (1.18)  −2.2 (0.71) Change frombaseline, LS mean (SE) −0.9 (0.1)  −1.3 (0.2) −1.1 (0.2) −1.5 (0.2) −1.7(0.2) −2.1 (0.2) LSM difference (SE)a −0.4 (0.3) −0.2 (0.3) −0.6 (0.3)−0.8 (0.3) −1.2 (0.3) p value 0.0973 0.3609 0.0272 0.0029 <0.0001Uncooperativeness Baseline, Mean (SD) 3.3 (0.72)  3.2 (0.81)  3.3 (0.83) 3.4 (0.92)  3.4 (0.70)  3.2 (0.81) 2 hours post-dose Mean (SD) 2.5(0.97)  2.0 (0.84)  2.2 (0.94)  2.0 (1.24)  1.7 (0.91)  1.4 (0.62)Change from baseline, mean (SD) −0.8 (0.98)   −1.2 (1.06)  −1.1 (1.11) −1.4 (1.33)  −1.8 (1.06)  −1.8 (0.81) Change from baseline, LS mean(SE) −0.8 (0.1)  −1.3 (0.2) −1.1 (0.2) −1.4 (0.2) −1.7 (0.2) −1.8 (0.2)LSM: difference (SE)a −0.5 (0.3) −0.3 (0.3) −0.6 (0.3) −1.0 (0.3) −1.0(0.3) p value 0.0669 0.2607 0.0268 0.0004  0.0001 Excitement Baseline,Mean (SD) 3.8 (0.64)  3.5 (0.62)  3.6 (0.70)  3.5 (0.62)    3.8 (0.7.1) 3.9 (0.64) 2 hours post-dose Mean (SD) 2.7 (1.07)  2.3 (0.83)  2.3(1.24)  2.1 (1.37)  1.9 (1.06)  1.6 (0.70) Change from baseline, mean(SD) −1.1 (1.11)   −1.2 (0.88)  −1.2 (1.22)  −1.4 (1.46)  −1.9 (1.02) −2.3 (0.77) Change from baseline, LS mean (SE) −1.1 (0.2)  −1.3 (0.2)−1.3 (0.2) −1.5 (0.2) −1.8 (0.2) −2.2 (0.2) LSM difference (SE)a −0.2(0.3) −0.2 (0.3) −0.4 (0.3) −0.8 (0.3) −1.2 (0.3) p value 0.3967 0.4.3940.1577 0.0081 <0.0001

Secondary Efficacy Endpoints:

Changes in secondary efficacy measures (i.e., ACES and CGI-I scores) at2 hours post-dose were consistent with the results for PEC total scoresand were indicative of improvement in symptoms of agitation aftertreatment with dexmedetomidine sublingual film.

ACES scores: A secondary objective for this study was to evaluate theduration of calming effect of dexmedetomidine sublingual thin film drugutilizing the Agitation-Calmness Evaluation Scale (ACES) collected atpre-dose, 2 hr, and 4 hr after first dose. The ACES assessment wasconsistent with the analysis of the primary endpoint, and metstatistically significance for calming as measured by ACES at two hourscompared to placebo in the three highest doses evaluated (80 μg;p=0.0150), (120 μg; p=0.0003) and (180 μg; p<0.0001). At 2 hours afterdosing, subjects in the 80 μg, 120 μg, and 180 μg treatment groupsshowed significantly greater improvements relative to placebo in ACESscores (+2.3 [P=0.0150], +3.1 [P=0.0003], and +4.2 [P=<0.0001],respectively, compared to placebo of +1.2). The improvements at 4 hourspost-dose were similar (+2.1 [P=0.0252], +3.2 [P=<0.0001], and +4.1[P=<0.0001], placebo was +1.1). (Table 15 and FIG. 3 ). In terms ofcalming effect (as measured by ACES scores), mean scores in 120 μg and180 μg groups increased from a baseline of approximately 2 “moderateagitation” to 5.1 “mild calmness” and 6.2 “moderate calmness”,respectively at 2 hours post-dose, compared with a score of 3.4 “mildagitation” in the placebo group. The improvements in calmness in thegroups were statistically significant with P values of 0.0003 and<0.0001, respectively, compared with placebo (Table 15).

Time to resolution of agitation: The percentage of subjects achieving anACES score of at least 4 (normal)) at 2 and 4 hours post dosing isdisplayed in FIGS. 3. At 2 and 4 hours after dosing, the percentage ofsubjects who achieved a ACES score of at least 4, which indicatedresolution of agitation, was significantly greater in the 120 μg group(72.2% [P=0.0045] and 77.8% [P=0.0016], respectively) and the 180 μggroup (88.9% [P<0.0001] and 83.3% [P=0.0002], respectively) comparedwith the placebo group (31.1% at both 2 and 4 hours post-dose). In termsof sedation (as measured by ACES scores) the results indicated that atotal of 9 subjects in the treatment groups had scores of 8 “deep sleep”at 2 hours and/or 4 hours post-dose, however, no subject in any of thetreatment groups had a score of 9 “unarousable.” (Table 16). Calmingeffect was durable lasting at least 6 hours as evidenced by separationfrom placebo for 80 μg, 120 μg and 180 μg dose groups.

TABLE 15 Change from Baseline in ACES Score at 2 and 4 hours post dosing(Intent to treat population) Dexmedetomidine Sublingual Film Placebo 20μg 60 μg 80 μg 120 μg 180 μg Time Post dose (N = 45) (N = 18) (N = 18)(N = 18) (N = 18) (N = 18) Baseline, n Mean (SD) 2.1 (0.55) 2.3 (0.49)2.2 (0.55) 2.2 (0.55) 2.0 (0.34) 1.9 (0.54) 2 hours post-dose Mean (SD)3.4 (1.55) 3.8 (1.11) 4.2 (1.70) 4.6 (2.25) 5.1 (2.05) 6.2 (1.58) Changefrom baseline, mean (SD)^(a) 1.2 (1.46) 1.4 (1.29) 2.0 (1.71) 2.3 (2.43)3.1 (2.03) 4.2 (1.83) Change from baseline, LS mean (SE)^(b) 1.2 (0.3) 1.6 (0.4)  2.1 (0.4)  2.4 (0.4)  3.0 (0.4)  4.1 (0.4)  LSM difference(SE)^(c) 0.4 (0.5)  0.8 (0.5)  1.2 (0.5)  1.8 (0.5)  2.9 (0.5) P-value^(d) 0.4371 0.0795 0.0150  0.0003 <0.0001 4 hours post-dose Mean(SD) 3.2 (1.42) 4.4 (1.54) 3.9 (1.76) 4.3 (2.22) 5.2 (1.72) 6.0 (1.75)Change from baseline, mean (SD)^(a) 1.1 (1.40) 2.1 (1.53) 1.7 (1.81) 2.1(2.19) 3.2 (1.69) 4.1 (2.04) Change from baseline, LS mean (SE)^(b) 1.1(0.3)  2.3 (0.4)  1.8 (0.4)  2.2 (0.4)  3.1 (0.4)  3.9 (0.4)  LSMdifference (SE)^(c) 1.2 (0.5)  0.7 (0.5)  1.1 (0.5)  2.0 (0.5)  2.8(0.5)  P-value^(d) 0.0164 0.1524 0.0252 <0.0001 <0.0001 ^(a)Change frombaseline (pre-dose) ACES score, with positive values in favor ofimprovement. ^(b)Least square mean and standard error per treatmentgroup. ^(c)Treatment Effect: Least square mean difference, standarderror, and 95% confidence intervals between Dexmedetomidine sublingualfilm and Placebo. ^(d)p value comparing Dexmedetomidine sublingual filmand Placebo

TABLE 16 Subjects Rates with an ACES Scores of 8 (Deep Sleep) or 9(Unarousable Sleep) for all dose groups Number of Number of Number ofSubjects Subjects Subjects ACES Score Dose Group at Baseline at 2 hr at4 hr Deep Sleep Placebo 0 0 0 ACES Scores = 8 20 μg 0 0 1 60 μg 0 0 0 80μg 0 1 1 120 μg 0 2 0 180 μg 0 2 3 Unarousable Sleep Placebo 0 0 0 ACESScore = 9 20 μg 0 0 0 60 μg 0 0 0 80 μg 0 0 0 120 μg 0 0 0 180 μg 0 0 0

CGI-I scores: Mean baseline CGI-S scores were comparable across alltreatment groups (range: 3.9 to 4.3). The CGI-S scores indicated thatthe subjects were clinically agitated (ie, moderately ill) prior todosing (Table 17). Significant improvements in agitation (ie, lowerCGI-I scores) from baseline were observed at 1 hour after dosing in thedexmedetomidine sublingual film 120 μg and 180 μg groups. Mean (SD)scores were 2.3 (1.13) and 2.1 (0.87), respectively, compared with 3.0(0.98) in the placebo group (Table 18). LSM differences from placebowere −0.7 (P=0.0167) and −0.9 (P=0.0019) in the 120 μg and 180 μggroups, respectively. Significant improvements in agitation (i.e. lowermean CGI-I scores) from baseline were observed at 2 hours post-dose inthe 120 μg group (1.9 [P=0.0007]) and in the 180 μg group (1.4[P<0.0001]), compared with a mean score of 3 in the placebo group (Table18). LSM differences from placebo were −1.1 (P=0.0007) and −1.6(P<0.0001). Significant improvements were also observed at 4 hourspost-dose in the dexmedetomidine sublingual film 120 μg and 180 μggroups The percentage of subjects achieving CGI-I scores of 1 or 2(‘very much improved’ or ‘much improved’) at 2 hours post-dose wassignificantly higher in the 120 μg group (66.7% [P=0.0125]) and in the180 dose group (94.4% [P<0.0001]), compared with placebo (31.0%).Significant improvements were also observed at 1 hour and at 4 hoursafter dosing for both treatment groups (Table 19 and FIG. 4 ).

TABLE 17 CGI-S Mean Scores at Baseline (Intent to treat Population)Dexmedetomidine Sublingual Film Time Point Placebo 20 μg 60 μg 80 μg 120μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N =18) Number of subjects 45 18 18 18 18 18 Baseline (pre-dose) Mean (SD)4.2 (0.44) 3.9 (0.47) 4.1 (0.68) 4.1 (0.32) 4.3 (0.57) 4.3 (0.46)Minimum-Maximum 3.0-5.0 3.0-5.0 3.0-5.0 4.0-5.0 3.0-5.0 4.0-5.0

TABLE 18 Summary of Change from Baseline for CGI-I Score (Intent totreat Population) Dexmedetomidine Sublingual Film Time Point Placebo 20μg 60 μg 80 μg 120 μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N =18) (N = 18) (N = 18) Number of subjects 45 18     18     18     18    18     30 minutes post-dose Mean (SD) 3.1 (1.04)  3.1 (0.76)  2.8 (1.15) 3.2 (1.15)  3.1 (0.76)  3.1 (0.76) LS mean (SE)^(a) 3.2 (0.1)  3.1(0.2) 2.8 (0.2) 3.2 (0.2) 3.1 (0.2) 3.1 (0.2) LSM difference (SE)^(b)−0.1 (0.3)  −0.4 (0.3)  −0.0 (0.3)  −0.1 (0.3)  −0.1 (0.3)  P-value^(c)0.7431 0.1778 0.9022 0.7431 0.7431 1 hour post-dose Mean (SD) 3.0 (0.98) 2.9 (0.83)  2.4 (1.20)  2.8 (1.42)  2.3 (1.13)  2.1 (0.87) LS mean(SE)^(a) 3.0 (0.2)  2.9 (0.3) 2.4 (0.3) 2.8 (0.3) 2.3 (0.3) 2.1 (0.3)LSM difference (SE)^(b) −0.1 (0.3)  −0.6 (0.3)  −0.2 (0.3)  −0.7 (0.3) −0.9 (0.3)  P-value^(c) 0.7098 0.0645 0.5769 0.0167 0.0019 2 hourspost-dose Mean (SD) 3.0 (1.09)  2.4 (0.98)  2.3 (1.13)  2.6 (1.54)  1.9(1.00)  1.4 (0.61) LS mean (SE)^(a) 3.0 (0.2)  2.4 (0.3) 2.3 (0.3) 2.6(0.3) 1.9 (0.3) 1.4 (0.3) LSM difference (SE)^(b) −0.6 (0.3)  −0.7(0.3)  −0.4 (0.3)  −1.1 (0.3)  −1.6 (0.3)  P-value^(c) 0.0701 0.01900.2034 0.0007 <0.0001  4 hours post-dose Mean (SD) 3.0 (1.08)  2.4(0.92)  2.8 (1.22)  2.6 (1.60)  1.8 (0.73)  1.4 (0.62) LS mean (SE)^(a)3.0 (0.2)  2.4 (0.3) 2.8 (0.3) 2.7 (0.3) 1.8 (0.3) 1.4 (0.3) LSMdifference (SE)^(b) −0.6 (0.3)  −0.2 (0.3)  −0.3 (0.3)  −1.2 (0.3)  −1.5(0.3)  P-value^(c) 0.0516 0.5071 0.4139 0.0001 <0.0001  Clinical GlobalImpression-Improvement scores range from 1 (Very much improved) to 7(Very much worse). Test statistics and estimates are from a restrictedmaximum likelihood repeated measures mixed model on observed values withtimepoint and its interaction with treatment group as repeated measuresusing an unstructured covariance structure. ^(a)Least square mean andstandard error per treatment group. The corresponding estimates for theplacebo group are not included as they vary with the dexmedetomidinesublingual film dosing group being compared. ^(b)Treatment Effect: Leastsquare mean difference, standard error, and 95% confidence intervalsbetween dexmedetomidine sublingual film and Placebo ^(c)P valuecomparing dexmedetomidine sublingual film and Placebo

TABLE 19 Percent of Responders in the CGI-I Scale over Time(Intent-to-Treat Population) Dexmedetomidine sublingual film Time PointPlacebo 20 μg 60 μg 80 μg 120 μg 180 μg Statistics (N = 45) (N = 18) (N= 18) (N = 18) (N = 18) (N = 18) 30 minutes post-dose Percent 22.2%22.2% 38.9% 27.8% 22.2% 22.2% responders P-value^(a) 1.000  0.21580.7457 1.000  1.000 1 hour post-dose Percent 24.4% 38.9% 44.4% 44.4%55.6% 72.2% responders P-value^(a) 0.3549 0.1383 0.1383 0.0361   0.00112 hours post-dose Percent 31.1% 55.6% 55.6% 50.0% 66.7% 94.4% respondersP-value^(a) 0.0896 0.0896 0.2462 0.0125 <0.0001 4 hours post-dosePercent 32.6% 55.6% 44.4% 57.1% 83.3% 94.4% responders P-value^(a)0.1499 0.3968 0.1231 0.0005 <0.0001 ^(a)P-value based on a comparison ofdexmedetomidine sublingual film versus placebo via a Fisher’s exact test

Pharmacokinetic Results:

Pharmacokinetic analysis was conducted using a validated install ofPhoenix® WinNonlin® version 8.1. Non-compartmental analysis was alsoconducted on the final audited data which consisted of a total of 135participants in 5 cohorts receiving 20, 60, 80 (1×20 μg films and 1×60μg films), 120 (2×60 μg films) and 180 μg (3×60 μg films) ofdexmedetomidine sublingual film. Measurable concentrations ofdexmedetomidine were observed at the first collected post dose plasmasample (1 hr) for all dose levels and tabulated in table 20. There wereno measurable concentrations at pre-dose (0 hr) at any dose level.Measurable concentrations of dexmedetomidine were observable until 8 hrfor all dose levels with measurable concentrations at 24 hr in somesubjects at each dose level (Table 20; Error! Reference source notfound. A and 5B). Dexmedetomidine sublingual film is absorbed rapidlywith maximum concentration achieved on average within about 2.5 hoursafter administration. The median Tmax ranged from 1.50-2.31 hr while themedian t1/2 ranged from 2.36-3.06 hr across the 5 dose levels. Theexposure (Cmax and AUC) increased in an approximately dose proportionalmanner within the dose range (20 μg −180 μg) studied after singleadministration. The median Cmax ranged from about 40 ng/L to about 500ng/L. After absorption, it was eliminated with about a 3-hour half-lifewhich was consistent across dose groups. In 20 μg dose group, 8 of 18subjects were given a second dose of dexmedetomidine sublingual film,the exposure (Cmax and AUC) was about 2-fold higher than in the groupwhich was not redosed

Observed exposures following a single dose of 180 μg (Mean Cmax: 379ng/L; Mean AUC 2881 ng/L) (Table 20) are significantly below the meanexposures (IV PRECEDEX® at approved dose is estimated): Cmax: 1339 ng/L;AUC: 31713 ng·h/L (PKPD18-1054) with the highest approved dose ofdexmedetomidine.

TABLE 20 Individual and summary statistics of PK parameter estimates ofdexmedetomidine in plasma after administration of dexmedetomidinesublingual film in schizophrenia patients. Dose Re- Cmax Tmax AUClastAUCinf_obs t½ Cohort (ug) dose Subject ID (ng/L) (hr) (hr*ng/L)(hr*ng/L) (hr) 1 20 No 01-001 35.54 1.50 224.01 NC NC 01-002 38.55 1.50186.08 NC 3.79 01-010 59.82 1.00 104.40 NC 2.12 01-026 14.07 4.02 57.43NC NC 07-015 33.41 1.53 177.60 NC 5.36 07-030 34.31 2.00 176.11 203.812.29 10-027 35.38 2.00 184.37 NC 3.64 23-016 69.05 1.48 264.45 NC 2.9523-018 40.37 1.97 154.62 186.40 3.17 23-020 38.49 1.95 190.81 226.262.51 N 10 10 10 3 8 Mean 39.90 1.89 171.99 205.49 3.23 SD 15.02 0.8157.74 19.98 1.05 CV % 37.64 42.89 33.57 9.72 32.61 Min 14.07 1.00 57.43186.40 2.12 Median 37.02 1.74 180.99 203.81 3.06 Max 69.05 4.02 264.45226.26 5.36 Geometric 37.16 1.78 160.36 204.85 3.09 Mean Geometric 43.8936.99 45.49 9.72 31.23 CV % 1 20 Yes 01-009 130.44 2.00 662.46 NC 3.9401-013 122.23 2.00 486.82 563.33 2.73 05-007 49.87 2.50 230.06 NC 4.0205-008 66.64 2.12 272.47 304.52 2.00 05-021 86.86 2.50 410.74 NC 3.1005-023 52.29 2.50 236.04 NC NC 05-024* 138.69 8.03 1912.52 NC NC 07-028125.70 2.00 476.62 519.25 1.81 N 8 8 8 3 6 Mean 96.59 2.96 585.96 462.372.93 SD 36.95 2.06 556.20 138.47 0.94 CV % 38.26 69.85 94.92 29.95 31.98Min 49.87 2.00 230.06 304.52 1.81 Median 104.54 2.31 443.68 519.25 2.91Max 138.69 8.03 1912.52 563.33 4.02 Geometric 89.71 2.61 453.42 446.602.80 Mean Geometric 44.50 49.35 78.77 34.37 34.49 CV % 2 60 No 01-04493.67 1.00 442.23 NC 3.10 01-047 73.42 1.00 265.85 293.67 01-055 113.351.50 474.46 562.60 2.87 01-056 154.79 1.50 413.53 428.64 1.48 03-03683.52 1.55 347.11 369.07 1.62 05-050 121.52 1.00 355.87 381.27 1.8405-052 105.84 1.50 330.30 369.14 2.36 06-033 253.14 1.45 737.87 834.442.27 06-034 206.42 1.53 887.27 1007.71 2.35 06-041 144.27 2.07 1714.291882.10 6.98 06-043 186.40 1.02 748.96 877.63 2.53 07-048 201.12 0.98874.85 1030.25 2.81 08-046* 93.22 2.00 346.61 NC NC 09-042 146.17 3.952072.02 2195.38 5.43 10-032 136.25 1.50 650.22 NC NC 10-035 127.27 1.50519.54 616.68 2.78 10-039 144.93 1.00 603.55 691.00 2.27 10-045 127.301.50 495.69 548.50 2.30 N 18 18 18 15 16 Mean 139.59 1.53 680.71 805.852.83 SD 47.22 0.69 481.66 555.95 1.42 CV % 33.83 45.0 70.76 68.89 50.15Min 73.42 0.98 265.85 293.67 1.48 Median 131.78 1.50 507.61 616.68 2.36Max 253.14 3.95 2072.02 2195.38 6.98 Geometric 132.56 1.43 575.95 674.142.60 Mean Geometric 33.88 36.02 59.93 65.01 40.94 CV % 3 120 No 01-059128.89 2.00 1143.72 1192.51 5.28 01-062 380.78 2.00 2927.15 2958.80 3.6401-065 393.58 4.00 3935.47 4063.95 4.62 01-080 316.57 1.00 1536.771538.84 2.60 01-082 315.51 4.00 4156.65 4371.55 5.32 01-086 201.58 1.00915.85 918.48 2.56 03-068 308.19 1.02 1039.39 1039.79 2.02 06-077 108.843.82 585.94 586.93 2.59 06-078 228.53 1.47 NC NC NC 06-083 154.65 1.47592.96 593.28 2.01 06-084 160.33 1.47 682.91 683.47 2.59 07-066 366.092.00 3920.86 4012.15 4.35 10-063 184.22 2.00 NC NC 3.50 10-076 149.112.00 990.19 989.76 2.81 23-069 286.88 2.00 1230.19 1230.90 1.98 23-070243.63 1.52 NC NC 3.21 23-073* 125.62 4.00 NC NC NC 23-074 233.12 1.551162.59 1166.09 2.83 N 18 18 18 14 16 Mean 238.12 2.13 1513.91 1810.473.25 SD 92.98 1.06 1264.13 1395.65 1.1 CV % 39.05 50.03 83.50 77.0934.27 Min 108.84 1.00 499.50 586.93 1.98 Median 230.83 2.00 970.381179.30 2.82 Max 393.58 4.00 4158.05 4371.55 5.32 Geometric 220.53 1.911169.33 1411.79 3.08 Mean Geometric 42.89 49.10 78.73 81.15 33.71 CV % 4180 No 01-089 490.60 1.00 5498.99 5592.92 3.92 01-097 636.45 1.502508.31 2676.44 1.76 01-105 685.45 1.00 2628.09 3126.77 2.73 01-111*88.10 8.00 1311.33 NC NC 05-088 127.77 1.02 520.53 569.19 2.03 05-098563.94 1.47 2435.38 2644.08 1.86 05-100 487.88 1.47 4630.43 4705.04 3.9006-091 592.99 3.98 6835.79 7310.47 5.92 06-093 406.57 2.07 2173.00 NC3.22 07-095* 443.70 2.00 1911.81 NC NC 10-090 546.65 2.00 3808.10 NC5.19 10-123 797.37 1.50 8928.20 9468.70 5.80 10-127 640.01 2.00 2444.452746.20 2.30 10-129 483.07 2.00 3578.09 4340.66 9.65 23-103 225.12 1.981034.07 1140.28 1.90 23-104 227.51 1.97 1086.53 NC 2.94 23-125 237.951.98 943.23 1049.33 2.10 23-126 224.88 1.98 1243.11 NC 2.84 N 18 18 1812 16 Mean 439.22 2.16 2973.31 3780.85 3.63 SD 206.41 1.60 2255.102663.22 2.12 CV % 46.99 73.99 75.84 70.44 58.29 Min 88.10 1.00 520.53569.19 1.76 Median 485.48 1.98 2439.91 2936.49 2.89 Max 797.37 8.008928.20 9468.70 9.65 Geometric 379.13 1.87 2294.38 2881.18 3.20 MeanGeometric 68.19 52.19 87.67 100.34 53.08 CV % 5 80 No 01-144 160.18 2.00784.24 917.99 2.49 02-133 142.99 2.03 747.42 886.35 2.41 02-142 222.792.00 2480.66 2594.62 5.37 03-112 68.41 1.55 416.50 NC NC 03-114 70.461.03 244.38 NC NC 03-120 107.00 1.53 450.79 531.82 2.67 03-134 135.301.55 759.89 894.79 2.57 08-092 167.57 1.88 938.26 NC NC 08-094 199.631.45 684.60 737.33 1.88 08-109 102.29 1.50 561.56 NC 3.12 09-137 151.892.25 635.19 767.51 3.07 20-115 224.70 1.22 1114.91 1366.03 2.72 20-138175.94 4.32 2218.17 2334.99 5.33 20-140 182.32 1.58 659.20 702.28 1.7820-141 253.29 1.20 888.38 NC 4.75 22-131 184.62 2.12 1020.28 NC 2.9624-116 315.11 1.53 1145.23 1305.66 2.53 24-130 139.94 4.03 1325.851375.38 4.93 N 18 18 18 12 15 Mean 166.91 1.93 948.64 1201.23 3.24 SD62.75 0.88 579.45 651.50 1.22 CV % 37.59 45.71 61.08 54.24 37.76 Min68.41 1.03 244.38 531.82 1.78 Median 163.88 1.57 772.07 906.39 2.72 Mas315.11 4.32 2480.66 2594.62 5.37 Geometric 155.27 1.79 816.58 1071.373.05 Mean Geometric 42.27 38.50 60.56 51.21 36.76 CV %

3. Safety and Tolerability:

Dexmedetomidine sublingual film (formulations of Example 1 and 2) waswell tolerated and had a favourable safety profile in the treatment ofsubjects with agitation. An overview of subjects who experienced atleast 1 treatment emergent adverse event (TEAE) by treatment group forthe safety population is given in Tables 21 and 22. Overall, a total of55 subjects (40.7% [ 55/135]) experienced a least 1 TEAE. The proportionof subjects who experienced TEAEs was similar in the 80 μg, 120 μg, and180 μg dose groups (55.6%, 66.7%, and 66.7%, respectively). Incomparison, the proportion of subjects with TEAEs was lower in the 20 μgand 60 μg dose groups (27.8% and 33.3%, respectively) and the placebogroup (22.2%). Most (81.1%) of the TEAEs in all treatment groups weremild in severity. Almost all (90.9%) of the TEAEs were considered to berelated to study drug in all treatment groups. None of the subjectsexperienced a TEAE that was considered to be severe in intensity. Therewere no deaths, SAEs, or discontinuations due to an AE reported in thisstudy (Tables 21 and 22).

The TEAEs reported in this study were consistent with known common sideeffects of dexmedetomidine, namely, dry mouth, bradycardia, hypotension,and somnolence (Table 21).

The most frequently reported TEAE was somnolence with 26 subjectsexperiencing the event of which 20 events were mild in severity and 4events were moderate in severity. Incidences for somnolence in thegroups were 16.7% (20 μg and 60 μg), 22.2% (120 μg), 33.3% (80 μg), and44.4% (180 μg); incidence in the placebo group was 4.4%. The second mostfrequently reported TEAE was dry mouth which was reported by 5.6%,16.7%, 16.7%, and 11.1% of subjects in the 20 μg, 80 μg, 120 μg, and 180μg groups, respectively, compared with 13.3% of subjects in the placebogroup. No subject in the 60 μg dose group reported an event of drymouth. All cases of dry mouth were mild in severity.

In the dexmedetomidine hydrochloride treatment groups, TEAEs associatedwith vital signs were: hypotension in 6 subjects (n=2 [120 μg], n=4 [180μg], orthostatic hypotension (n=1 [80 μg], n=1 [120 μg], and n=1 [180μg]), and bradycardia (n=1 [20 μg]). All subjects recovered from theevents.

Three laboratory related adverse events (3× upper limit of normal for TBili, 3+Glucose in urine, and 4+ Protein in urine) were beingfollowed-up at each respective clinical site and remained unresolved atthis time. Otherwise there were no clinically significant changes inlaboratory parameters and ECG assessments. No physical examinationfinding was considered clinically significant by the investigators. Noneof the subjects had a negative reaction (i.e. local irritation) to studydrug as determined by buccal examination.

Also, the dose dependent decreases in SBP and DBP were observed withmaximum changes at 2 hours post-dose:

-   -   SBP: −4.6 (9.63), −5.6 (10.85), −8.2 (11.50), −12.1 (20.50), and        −14.7 (12.09) mmHg in the 20 μg, 60 μg, 80 μg, 120 μg, and 180        μg groups, respectively, and +1.2 (9.23) mmHg in the placebo        group.    -   DBP: 0.3 (10.39), −5.3 (7.86), −6.4. (8.05), −7.8 (9.40), and        −6.6 (6.41) mmHg in the 20 μg, 60 μg, 80 μg, 120 μg, and 180 μg        groups, respectively, and +0.2 (7.82) mmHg in the placebo group.    -   HR: −0.1 (6.24), −3.9 (9.13), −0.8 (8.39), −2.2 (13.03), and        −10.7 (12.97) bpm in the 20 μg, 60 μg, 80 μg, 120 μg, and 180 μg        groups, respectively, and −0.8 (8.29) bpm in the placebo group.

Further, the orthostatic measurements of SBP, DBP, and HR were performedafter the subject had been standing for a total of 5 minutes.

Mean changes from baseline at hours 2 post dosing for standing SBP, DBP,and HR are provided below (FIGS. 7A, 7B and 7C). These changes aresimilar to the changes from baseline values for resting measurements forSBP, DP, and HR (FIGS. 6A, 6B and 6C). Total of 3 subjects (1 in eachdose groups 80 μg, 120 μg, and 180 μg) experienced TEAEs of orthostatichypotension.

Mean (±SD) changes from baseline at 2 hours post dosing for standingSBP, DBP, and HR were:

-   -   SBP: −3.1 (8.34), −4.6 (9.04), −12.6 (12.83), −11.9 (16.43) and        −15.0 (11.3) mmHg in the 20 μg, 60 μg, 80 μg, 120 μg, and 180 μg        dose groups, respectively, and +0.5 (8.35) mmHg in the placebo        group.    -   DBP: −1.4 (6.97), −4.2 (4.78), −6.7 (8.49), −6.9 (7.86), and        −7.1 (8.51) mmHg in the 20 μg, 60 μg, 80 μg, 120 μg, and 180 μg        dose groups, respectively, and −1.3 (7.36) mmHg in the placebo        group.    -   HR: 0.6 (7.92), −4.3 (11.87), −1.1 (10.47), −1.7 (13.98), and        −10.4 (10.08) bpm in the 20 μg, 60 μg, 80 μg, 120 μg, and 180 μg        dose groups, respectively, and −0.3 (9.88) bpm in the placebo        group.

TABLE 21 Treatment Emergent Adverse Events by System Organ Class andPreferred Term During the Treatment Period(Safety Population)Dexmedetomidine sublingual film System Organ Class Placebo 20 μg 60 μg80 μg 120 μg 180 μg Preferred Term (N = 45) (N = 18) (N = 18) (N = 18)(N = 18) (N = 18) Any AEs 10 (22.2) 5 (27.8)  6 (33.3) 10 (55.6) 12(66.7) 12 (66.7)  Nervous system disorders  6 (13.3) 4 (22.2)  4 (22.2) 8 (44.4)  9 (50.0) 9 (50.0) Somnolence 2 (4.4) 3 (16.7)  3 (16.7)  6(33.3)  4 (22.2) 8 (44.4) Headache 2 (4.4) 1 (5.6)  0 1 (5.6)  3 (16.7)0 Dizziness 2 (4.4) 0  2 (11.1) 1 (5.6) 1 (5.6) 0 Paraesthesia 0 0 0 1(5.6) 1 (5.6) 0 Hypoaesthesia 0 0 1 (5.6) 0 0 0 Sedation 0 0 0 0 0 1(5.6)  Gastrointestinal disorders  7 (15.6) 2 (11.1) 1 (5.6)  4 (22.2) 4 (22.2) 2 (11.1) Dry mouth  6 (13.3) 1 (5.6)  0  3 (16.7)  3 (16.7) 2(11.1) Constipation 0 0 1 (5.6) 1 (5.6) 0 0 Diarrhoea 0 0 0 0 1 (5.6) 0Dyspepsia 0 1 (5.6)  0 0 0 0 Nausea 1 (2.2) 0 0 0 0 0 Toothache 1 (2.2)0 0 0 0 0 Vascular disorders 0 0 0 1 (5.6)  3 (16.7) 5 (27.8)Hypotension 0 0 0 0  2 (11.1) 4 (22.2) Orthostatic hypotension 0 0 0 1(5.6) 1 (5.6) 1 (5.6)  Investigations 3 (6.7) 0 1 (5.6) 0 1 (5.6) 1(5.6)  Alanine aminotransferase increased 1 (2.2) 0 0 0 0 0 Aspartateaminotransferase increased 1 (2.2) 0 0 0 0 0 Blood bilirabin increased 00 1 (5.6) 0 0 0 Glucose urine present 0 0 0 0 1 (5.6) 0 Heart rateincreased 1 (2.2) 0 0 0 0 0 Liver function test increased 1 (2.2) 0 0 00 0 Protein urine present 0 0 0 0 0 1 (5.6)  Infections and infestations1 (2.2) 0 1 (5.6) 0 1 (5.6) 0 Cellulitis 0 0 0 0 1 (5.6) 0Nasopharyngitis 1 (2.2) 0 0 0 0 0 Urinary tract infection 0 0 1 (5.6) 00 0 Cardiac disorders 0 0 0 0 1 (5.6) 0 Bradycardia 0 0 0 0 1 (5.6) 0Musculoskeletal and connective 0 0 0 1 (5.6) 0 0 tissue disorders Painin extremity 0 0 0 1 (5.6) 0 0

TABLE 22 Summary of Adverse Events ( Safety Population) Dose groupsPlacebo 20 μg 60 μg 80 μg 120 μg 180 μg Category, n (%) (N = 45) (N =18) (N = 18) (N = 18) (N = 18) (N = 18) Any TEAE 10 (22.2) 5 (27.8) 6(33.3) 10 (55.6) 12 (66.7) 12 (66.7) Any treatment related TEAE 10(22.2) 4 (22.2) 5 (27.8) 10 (55.6) 10 (55.6) 11 (61.1) TEAE severityMild  8 (17.8) 5 (27.8) 5 (27.8)  9 (50.0) 11 (61.1)  7 (38.9) Moderate2 (4.4) 0 1 (5.6)  1 (5.6) 1 (5.6)  5 (27.8) Severe 0 0 0 0 0 0 Any SAE0 0 0 0 0 0 Any AE leading to discontinuation 0 0 0 0 0 0 Abbreviations:AE = adverse events; TEAE = treatment-emergent adverse event; SAE =serious adverse event Percentages are based on the number of SafetyPopulation subjects in each treatment arm. If a subject experienced morethan one adverse event in a category, the subject is counted only oncein that category.

Conclusion: Dexmedetomidine sublingual film treatment significantlyimproved the severity of agitation from baseline as measured by PEC,CGI-I, and ACES scales in schizophrenia patients. The primary efficacyendpoint was met in 80 μg, 120 μg, and 180 μg treatment groups as therewas significant improvements in PEC total scores from baseline at 2hours post-dose with mean changes of −7.3, −9.2, and −10.8 points,respectively, versus −4.5 for placebo. LSM differences from placebo were−2.9 (P=0.0210), −4.6 (P=0.0003), and −6.3 (P<0.0001) for the 80 μg, 120μg, and 180 μg groups, compared with placebo The proportion ofresponders (ie, a ≥40% decrease in PEC total score) at 2 hours post-dosewas significantly higher in the 120 μg and 180 μg dose groups (68.8%[P=0.0158]) and 94.4% [P<0.0001], respectively) compared with placebo(31.0%). Further, changes in secondary efficacy measures (ie, CGI-I andACES scores) at 2 hours post-dose were consistent with the results forPEC total scores and were indicative of improvement in symptoms ofagitation after treatment with Dexmedetomidine sublingual film.

EXAMPLE 4: A PHASE IB/II, MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBOCONTROLLED, ASCENDING DOSE FINDING, EFFICACY, PHARMACOKINETIC AND SAFETYSTUDY OF DEXMEDETOMIDINE HYDROCHLORIDE SUBLINGUAL FILM IN AGITATIONASSOCIATED WITH DEMENTIA

Primary Objective:

Describe the safety and tolerability of single doses of dexmedetomidinehydrochloride that are efficacious in treatment of acute agitationassociated with dementia.

Secondary Objective:

-   -   1. Describe the onset and magnitude of calming effects of        different doses of Dexmedetomidine hydrochloride on symptoms of        acute agitation associated with dementia compared to placebo.    -   2. Describe the duration of calming as measured by PEC and ACES.    -   3. Describe the tolerability and safety profile of        Dexmedetomidine hydrochloride, as determined by adverse events        and vital signs versus placebo.    -   4. Describe clinical effects as measured by the Clinician Global        Impression of Severity of agitation scale (CGI-S) and then        Improvement (CGI-I) after drug administration.    -   5. Describe the frequency of agitation using the Cohen Mansfield        Agitation Inventory (CMAI) at baseline, 1 hour and 2 hours post        dose.    -   6. Determine the approximate dissolution time of Dexmedetomidine        hydrochloride films in the sublingual space.    -   7. Assess the local tolerability via buccal examination after        dosing Dexmedetomidine hydrochloride film.    -   8. Describe the pharmacokinetics and exposure of dexmedetomidine        as delivered by sublingual Dexmedetomidine hydrochloride dosing.

Methodology: This is an adaptive Phase Ib trial design. It is arandomized, double-blind, placebo-controlled, multiple ascending dosestudy assessing efficacy, pharmacokinetics, safety and tolerability ofDexmedetomidine hydrochloride dosing in adult (65 years and older) malesand females with acute agitation associated with dementia.

The study will attempt to characterize a safe and tolerable dose rangein at least 30 subjects, (4:1 randomization to active: placebo) per doselevel, at each of the three dose levels, that results in a calmingeffect as measured using the Pittsburgh Agitation Scale (PAS) (Table23).

Evaluation of three doses of 30 μg, 60 μg and 90 μg are planned, with anoption to test different doses based on tolerability and safety. This isan adaptive design as doses selected for testing may be different fromthese, based upon safety reviews. Doses lower or higher may be chosen totest, and repeated, up to 180 μg within each cohort. Dexmedetomidinehydrochloride films may be divided in half if needed to deliverhalf-dose strengths. Except for the first dose cohort (30 μg), eachsubsequent dose level will be authorized after a safety review of theprevious dosing cohort. Dosing may be repeated in the case of persistentor recurrent agitation, if there is no significant improvement (CGI-I of1 or 2 as ‘very much’ or ‘much improved’) and no safety events evident.Dosing may be repeated up to a total of two repeat doses (at the samerandomization group Active:Placebo) for all cohorts except for 90 μgdose which can only be repeated once (total 180 μg) if necessary, at 2hours post first dose but only after the 2-hour assessments areconducted and only within 12 hours post first dose. Patients can only bere-dosed if they are hemodynamically stable, not hypotensive (must begreater than 90/60 diastolic/systolic) and not bradycardic (must begreater than 60 bpm). Patients also cannot be re-dosed if they areorthostatic (a drop of 20 points in either SBP or DBP) or if they areexperiencing an AE. Not only does this determine individual response toa single dose but determines if a given subject is responsive to asecond dose, and may respond to a greater dose, or could be categorizedas a non-responder to dexmedetomidine hydrochloride despite beingexposed to a greater total dose.

Periodic safety data reviews will be undertaken on an ongoing basis toreview all subjects assigned and dosed, as data and analyses becomeavailable. Dose escalation will be allowed unless a safety ortolerability issue becomes evident upon periodic regular safety review.

Patients enrolling at a site are sequentially assigned to the lowestdose cohort (including placebo) followed by enrollment assignment toincreasing dose cohorts. This sequential escalating adaptive enrollmentensures subject safety; the lowest dose cohort completes accrual first,higher dose cohorts complete last. In addition, those subjects assessedas requiring a second dose for efficacy provide early evidence ofsafety/tolerability of higher doses as they are effectively exposed todoses that approximate the next dose cohort. The majority of patientswill be enrolled and evaluated in lower dose cohorts before a higherdose cohort is initiated. Further, if evidence of intolerability arisesfrom analyses integrating PK, exposure and safety/tolerability of allsubjects and doses, the dose regimen may be altered, or a different dosemay be selected to test the hypothesis that a (typically lower) doseregimen is better tolerated. Eligible patients (those with any type ofdementia) may be identified in SNIFFs, mental health, psychiatric ormedical emergency services, including medical/psychiatric observationunits, or as newly admitted to a hospital setting for acute agitation oralready in hospital for chronic underlying conditions. Subjects willlikely remain in their facility while undergoing screening procedures toassess eligibility. Upon confirmation of eligibility, subjects will berandomized to Dexmedetomidine hydrochloride or placebo film. At thebeginning of each study session, a single dose of Dexmedetomidinehydrochloride film will be administered sublingually by the patient ifable with instructions from an unblinded staff member who will notparticipate in evaluation of safety or efficacy. The drug film will beretained in the sublingual cavity until dissolved. Participants willalso be evaluated for local irritation around the area where the film isplaced. Efficacy and safety assessments will be conducted periodicallybefore and after dosing. The next cohort will be dosed after completingaccrual of most prior panels, in accord with regular ongoing periodicsafety and PK review as eligible subjects are assigned, dosed, and databecomes available.

Vital signs and ECGs will be conducted at the time points indicated inthe schedule of events. Participants will be allowed water as desired 15minutes after completion of dosing. Safety and tolerability assessmentswill be continued until the morning of Day 3 (day of discharge) and willbe repeated on Day 7+2. Smoking will be permitted according to thesite's policies. After the 4 hr assessments are completed, at thediscretion of the PI, rescue therapy may be initiated using standard ofcare treatment which may include lorazepam 0.5-5 mg po/IM or anantipsychotic medication po/IM.

Any abnormal vital sign measurement, clinical laboratory test, physicalexamination finding, or ECG parameter deemed clinically significant bythe investigator will be repeated, including test results obtained onthe final study day or upon early termination. For any test abnormalitydeemed clinically significant, repeat analysis will be performed duringthe follow-up period and until the value returns to baseline (or withinnormal limits) or the investigator deems the abnormality to be of noclinical significance. Subjects presenting with a clinically significantUrinary Tract Infection (UTI) as determined by clinical laboratory testswill be excluded from the study.

Efficacy Assessments:

Efficacy measurements will be taken up to and including 24 hours postfirst dose. The effects of Dexmedetomidine hydrochloride on acuteagitation will be assessed by the following scales: Pittsburgh AgitationScale (PAS), the PANSS-EC (PEC), CMAI, CGI-Severity for Agitation andCGI-Improvement for Agitation. If there is no significant improvement inCGI (CGI-I of 1 or 2 as “very much” or “much improved”) and there are noevident safety concerns, a second film (of same assignment active vs.placebo) may be given.

Safety and Tolerability Assessments:

AEs, clinical laboratory tests, ECG, and vital signs will be monitored,and all observed and volunteered AEs will be recorded. Blood pressure,heart rate and ECG will be completed per schedule of assessments. Anyabnormal clinically significant (investigator determined) vital signmeasurement, clinical laboratory test, physical examination finding, orECG parameter will be repeated, until the value returns to baseline (orwithin normal limits) or the investigator deems the abnormality to be ofno clinical significance. Orthostatic assessments will follow the CDCguidelines for the elderly (e.g. blood pressure upon standing for 1 and3 minutes). Safety and tolerability assessments will be continued untilthe morning of Day 2 and Day 3 and will be repeated on Day 7+2.

TABLE 23 Arms and Interventions Arms Intervention Active Comparator:Drug: Sublingual film containing Cohort 1: 30 μg dexmedetomidinehydrochloride Cohort 1 consists of 10 patients out for the treatment ofagitation of whom 8 patients receive 30 μg associated with Dementia filmand the remaining 2 patients Drug: Placebo Film receive a placeboPlacebo film for dexmedetomidine hydrochloride Active Comparator: Drug:Sublingual film containing Cohort 2: 60 μg dexmedetomidine hydrochlorideCohort 2 consists of 10 patients out for the treatment of agitation ofwhom 8 patients receive 60 μg associated with Dementia film and theremaining 2 patients Drug: Placebo Film receive a placebo Placebo filmfor dexmedetomidine hydrochloride Active Comparator: Drug: Sublingualfilm containing Cohort 3: 90 μg dexmedetomidine hydrochloride Cohort 3consists of 10 patients out for treatment of agitation of whom 8patients receive 90 μg associated with Dementia film and the remaining 2patients Drug: Placebo Film receive a placebo Placebo film fordexmedetomidine hydrochloride

Number of Subjects (Planned)

At least 30 subjects (10 per cohort) will be enrolled at up to 3 studysites in the United States. However, it is possible that the sponsor mayopt to expand the number of sites and subjects per dose cohort (up to 80total patients) as the study progresses.

Subjects:

Eligible individuals with any form of dementia who have a history ofrecent agitation (6 months or less) or their legally authorizedrepresentative (LAR) will sign an informed consent. Upon confirmation ofeligibility, subjects will be randomized to either dexmedetomidinehydrochloride sublingual film or placebo film. Ten (10) subjects whoexhibit acute agitation associated with dementia in each cohort will beenrolled (4:1 randomization; e.g.: eight dexmedetomidine hydrochloridesublingual film, two placebo films). Once subjects become agitated, theywill proceed with Day 1 assessments.

TABLE 24 Schedule of Events Pre- Pre- Screening⁸ Screening DoseTreatment Evaluation Day 1 Time point Pre- Pre- −1 hr to 5 10 15 30 1 24 6 8 Activity treatment treatment time 0 min min min min hr hr hr hr hrInformed Consent X Medical History X X Demographics X X Weight X HeightX Mini-Mental State X exam Clinical Dementia X Rating Score PhysicalExam X X Safety Labs³ X UTI and pregnancy X ECG with rhythm X X X strip⁷Pulse oximetry X X X X X X X Resting vital signs² X X X X X X X X XOrthostatic vital signs² X X X X X X X X Inclusion/Exclusion X X Xcriteria Randomization X CMAI X X X X Study drug administration⁶ PAS X XX X X X X X PEC X X X X X X X ACES X X X X X CGI-Severity X X AgitationCGI-Improvement/ X X X X X change in Agitation C-SSRS X X Buccal (SL) XX X X X X assessment⁵ PK Sampling⁴ X X  X* X X Concomitant Meds X X X XX X X X X X X X Adverse Events X X X X X X X X X X X X Day 2 Follow-Up(+1) Day 3 Discharge Day 7 (+2) Time point 24 hr Activity (−9/+12 hr)End of Study Informed Consent Medical History Demographics Weight XHeight Mira-Mental Stale exam X Clinical Dementia Rating X ScorePhysical Exam X Safely Labs³ X X UTI and pregnancy ECG with rhythmstrip⁷ X Pulse oximetry X Resting vital signs² X Orthostatic vitalsigns² X Inclusion/Exclusion criteria Randomization CMAI X X X Studydrug administration⁶ PAS X X X PEC X X X ACES CGI-Severity Agitation XCGI-Improvement/ change in Agitation C-SSRS X Buccal (SL) assessment⁵ XPK Sampling⁴ X Concomitant Meds X X X Adverse Events X X X Notes to theSchedule of Events: ¹Pre-dose assessments will have a window of 60minutes prior to first dose. If possible, Pre-dose CMAI should beperformed within 45 min prior to dosing and PAS, PEC and CGI-S should beperformed within 15 min prior to dosing. Timing of all subsequentassessments is relative to the first dose. All post-dose assessmentswill have a window of −10/+20 minutes until 2 hours and ±30 minutesuntil 8 hours. All post-dose efficacy assessments should be conductedprior to any other assessments at each time point. ²Resting vital signs(SEP, DBP and HR) will be taken upon having the subject recumbent for 5min at Pre Screening. Screening, Pre-dose and at 30 min, 1, 2, 4 6, 8and 24 hours post first dose. Triplicate measurements to be performed incase of Systolic BP <90 mmHg, Diastolic BP <60 mmHg or Pulse <60 bpm.Orthostatic measurements (SBP, DBP, HR, respiratory rate andtemperature) will be taken upon having the subject stand, withmeasurements taken upon standing for 1 and 3 minutes, per CDC guidelinesfor elderly) at Pre Screening, Screening, Pre-dose, 30 min, 1, 2, 4, 8and 24 hours post first dose. Vital signs are to be done prior to PKsamples. ³Safety Labs will include chemistry, hematology, urinalysis,and UDS (local lab, only conducted at Pre Screening). Labs drawn within28 days prior to dosing may suffice with the exception of urine drugscreen. ⁴PK blood samples will be collected at 30 min, 1, 2, 4, 8-10hours (collect one sample between 8 and 10 hours) and 24 hr after firstdose. A sample may not be collected if the Physician indicates in sourcedocuments that the patient is in a mental slate that is not conducive toPK sample collection. Non-compliance or refusal of all or any PK drawwill not be exclusionary nor result in Early termination (ET). All PKcollections will have a window of ±10 minutes except for the 24-hourpost-dose collection which will have a window of ±1 hour. *For re-dosedsubjects only: PK blood sample will be collected at 2.5 hrs, post firstdose in addition to the oilier times. ⁵Buccal exam for local irritationand drug dissolution time will be performed by unblinded staff at 5, 10,15, 30 min, 2 h, 4 h and 24 hours post first dose. ⁶In theinvestigator’s clinical Judgement, the same randomized dose and or alower dose may be repeated after 2 hr post first dose assessments arecomplete, if there is persistent or recurrent agitation as measured by(improvement on the CGI-I) and in the absence of safety concerns. Dosescan be repeated twice in a span of 12 hours, except for the 90 μgcohort, which can only be repeated once. If necessary, placement ofstudy drug may be perforated by unblinded research staff member.Antihypertensives or other medications can be held on the day of studydrug administration at the discretion of the PI. ⁷ECG for pre-dose needsto be collected but if unable to be assessed it will not constitute aprotocol deviation. ECGs collected following treatment are to beperformed prior to PK assessments. ⁸Day 1 to be performed within 28 daysfrom Pre-Screening Assessments. If subject does not become agitatedwithin the 28-day window, they are considered a pre-screen failure.However, the subject can be rescreened once at the discretion of theinvestigator.

Diagnosis and Main Criteria for Eligibility:

Inclusion Criteria

-   -   1. Male and female patients 65 years and older.    -   2. Patients who have met DSM-5 criteria for neurocognitive        disorder, or dementia who have history of instances of acute        agitation.    -   3. History of agitation to the point that it impairs social        activities, requires staffing or medical intervention (kick,        bite, flailing, etc.), or impairs ability for functional        activities of daily living.    -   4. Patients who meet IPA diagnostic criterion for agitation.    -   5. Patients who are judged to be clinically agitated at Pre-dose        with a total score of ≥8 on the 4 items (aberrant vocalization,        motor agitation, aggressiveness, and resisting care) comprising        the Pittsburgh Agitation Scale (PAS).    -   6. Patients who have a score of ≥2 on at least 1 of the 4 items        on the Pittsburgh Agitation Scale (PAS).    -   7. Patients who read, understand and provide written informed        consent, or who have a Legally Authorized Representative (LAR).    -   8. Patients who are in good general health prior to study        participation as determined by a detailed medical history,        physical examination, 12-lead ECG, blood chemistry profile,        hematology, urinalysis and in the opinion of the Principal        Investigator.    -   9. Female participants, if of child-bearing potential and        sexually active, and male participants, if sexually active with        a partner of child-bearing potential, who agree to use a        medically acceptable and effective birth control method        throughout the study and for one week following the end of the        study. Medically acceptable methods of contraception that may be        used by the participant and/or his/her partner include        abstinence, birth control pills or patches, diaphragm with        spermicide, intrauterine device (IUD), condom with foam or        spermicide, vaginal spermicidal suppository, surgical        sterilization and progestin implant or injection. Prohibited        methods include: the rhythm method, withdrawal, condoms alone,        or diaphragm alone.

Exclusion Criteria

-   -   1. Patients with agitation caused by acute intoxication must be        excluded. Positive identification of non-prescription drugs        during urine screening excludes the subject.    -   2. Patients treated within 4 hours prior to study drug        administration with benzodiazepines, other sedatives, hypnotics        or oral or short-acting intramuscular antipsychotics must be        excluded.    -   3. Treatment with alpha-1 noradrenergic blockers, alpha        adrenergic antagonists within 8 hours prior to dosing.    -   4. No new chronic medications initiated in the past 14 days        prior to screening excluding over-the-counter products taken        sporadically.    -   5. Patients with significant risk of suicide or homicide per the        investigator's assessment, or any patient with an answer of        “yes” to item 4 or 5 on the CSSRS.    -   6. Patients who have hydrocephalus, seizure disorder, or history        of significant head trauma, subarachnoid bleeding, brain tumor,        encephalopathy, meningitis, or focal neurological findings, with        a recent large (non-microvascular) stroke, who may be considered        medically unstable or in recovery must be excluded. Patients        with a remote history of stroke may be included, regardless of        size/location.    -   7. History of clinically significant syncope or other syncopal        attacks, orthostatic hypotension within the past two years,        current evidence of hypovolemia, orthostatic hypotension (≥20        mmHg drop in systolic BP following 1 and 3 minutes of standing)        and bradycardia, a baseline (Pre-dose) heart rate of <60 beats        per minutes or systolic blood pressure <110 mmHg or diastolic        BP<70 mmHg must be excluded.    -   8. Patients with laboratory or ECG abnormalities considered        clinically significant by the investigator or qualified designee        [Advanced heart block (second-degree or above atrioventricular        block without pacemaker), diagnosis of Sick sinus syndrome] that        would have clinical implications for the patient's participation        in the study must be excluded.    -   9. Patients with serious or unstable or uncontrolled medical        illnesses must be excluded. These include current hepatic        (moderate-severe hepatic impairment), renal, gastro-enterologic,        respiratory, cardiovascular (including ischemic heart disease,        congestive heart failure), endocrinologic, or hematologic        disease.    -   10. Patients who have received an investigational drug within 30        days prior to the current agitation episode must be excluded.    -   11. Patients who are considered by the investigator, for any        reason, to be an unsuitable candidate for receiving        dexmedetomidine, or unable to use the sublingual film, must be        excluded; e.g. patients with a history of allergic reactions to        dexmedetomidine must be excluded.    -   12. Patients experiencing clinically significant pain, per        Investigator.

Method of Assigning Subjects to Treatment Groups

Upon confirmation of eligibility, subjects will be randomized toDexmedetomidine hydrochloride or placebo film. In each of the three-dosecohorts, 10 participants (8 drug treated, 2 placebo) will be randomized4:1 Dexmedetomidine hydrochloride film: Placebo. Study randomizationwill be computer generated.

Treatment Administration

Dosing may be achieved by cutting of a film, widthwise, directly in themiddle, to make a half dose. Dosing may also be achieved byadministration of 1 to 3 films [e.g. a 60 μg dose may be administeredwith a half of a 60 μg dose (30 μg) to make a 90 μg dose]. At thebeginning of each study session, patients will be instructed on how toself-administer the investigational product. If the patient canself-administer, he/she will self-administer the dose of Dexmedetomidinehydrochloride or placebo film sublingually under supervision of anunblinded staff member who will not participate in evaluation of safetyor efficacy. The investigational product will be retained in thesublingual cavity until dissolved. If sublingual administration is notpossible, the film may be placed inside the lower lip. The location ofthe placement of the film should be noted in the subject's chart.Objective buccal mucosal examination and time of film dissolution byunblinded study staff per Table 24 will be conducted.

Study Procedures

Subjects or their LAR will provide written informed consent, and assentas applicable, before any study-related procedures are initiated,including the cessation of prohibited concomitant therapy. The scheduleof events to be performed during the study is provided in Table 24.

Study Assessments

Efficacy: The effect of study drug will be evaluated using severalvalidated instruments as given below.

PANSS-Excited Component (PEC)

Agitation-Calmness Evaluation Scale (ACES)

Cohen Mansfield Agitation Inventory (CMAI):

Assessment of drug effect on frequency of acute agitation will be alsodone using the CMAI. The CMAI is a rating questionnaire consisting of 29behaviors each rated on a 7-point scale of frequency. It is possiblethat all 29 behaviors will not be relevant to a specific patient. Onlybehaviors manifested by the subject at baseline will be assessedthroughout the study resulting in a modified CMAI. Behaviors which arepresent immediately pre-dose will be rated throughout the post-dosetime-points. At each time-point after pre-dose, the rater will noteitems (behaviors) which were not manifested prior to dosing have notemerged since last CMAI assessment. Should they emerge, these itemsshall be included in ratings.

Pittsburgh Agitation Scale (PAS):

The Pittsburgh Agitation Scale (PAS) is an instrument based on directobservations of the patient that is developed to monitor the severity ofagitation associated with dementia. There are four Behavior Groupsobserved (using a 0 to 4-point scale) in the patient, AberrantVocalization, Motor Agitation, Aggressiveness, Resting Care.

CGI-S and CGI-I for Agitation:

Both CGI-I and CGI-S will be focused on the severity of agitation ratherthan the severity of the overall illness of dementia.

Clinical Global Impression of Severity (CGI-S) will be rated based uponthe severity of agitation at screening and pre-dose (immediately priorto start of dosing).

Severity of agitation will be assessed based on following scale:

-   -   0=Not assessed    -   1=Normal not at all symptomatic    -   2=Minimally symptomatic-few or mild symptoms-little interference        with patients functioning    -   3=Mildly symptomatic-low level of symptoms-little interference        in social functioning    -   4=Moderately symptomatic-some prominent symptoms-some        interference in functioning    -   5=Markedly symptomatic-significant symptoms with very        substantial interference in functioning    -   6=Severely symptomatic-very marked symptoms make it difficult        for patients to engage with others    -   7=Among the most extremely symptomatic subjects-extreme        symptoms-patient is incapacitated or highly dangerous to self or        others requires extra care and supervision

Drug response on agitation will be evaluated by the Clinical GlobalImpressions—Improvement (CGI-I) which is performed after dosing andevaluated relative to pre-dose baseline agitation. The CGI-I scoresrange from 1 to 7:

-   -   0=not assessed (missing),    -   1=very much improved,    -   2=much improved,    -   3=minimally improved,    -   4=no change,    -   5=minimally worse,    -   6=much worse,    -   7=very much worse

Clinical Diagnosis and Description of Dementia:

The subtype of dementia will be determined and recorded based uponclinical neurologic and psychiatric evaluation to include review of allavailable medical information, medical records, documentation of priorevaluations, family/caretaker interviews, records, laboratory, geneticsor other biomarkers, and results of neuroimaging (if available). Thefollowing scales will characterize subject's dementia (DSM-5 MajorNeurocognitive disorder) in terms of cognitive and functionalimpairment:

MMSE

The Folstein Mini-Mental State Examination (MMSE) is an examination thattests an elderly person's cognitive ability. Domains measured by theMMSE include orientation to time and place, registration, attention andcalculation, recall, naming, repetition, comprehension, reading,writing, and drawing. Total points on this test is 30. Any score of 24or more (out of 30) indicates a normal cognition. Below this, scores canindicate severe (≤9 points), moderate (10-18 points) or mild (19-23points) cognitive impairment.

CDR®

The CDR® (Alzheimer's Disease Research Center, Washington University, StLouis) is a 5-point scale used to characterize six domains of cognitiveand functional performance applicable to Alzheimer Disease and relateddementias: memory, orientation, judgment & problem solving, communityaffairs, home & hobbies, and personal care. A score of 0 connotes nocognitive impairment, and then the remaining four points are for variousstages of dementia where:

-   -   CDR-0=normal    -   CDR-0.5=very mild dementia    -   CDR-1=mild    -   CDR-2=moderate    -   CDR-3=severe.

Safety

Safety will be assessed during the study by the monitoring and recordingof AEs, clinical laboratory test results (hematology, biochemistry, andurinalysis), vital sign measurements (systolic and diastolic bloodpressures, heart rate measured as pulse, respiratory rate, andtemperature), ECG, and physical examination findings.

Adverse events (AEs) will be characterized by type, severity,seriousness, and relationship to treatment. Adverse events will be codedby preferred term and system organ class using MedDRA version 20.0.

Pharmacokinetics

Blood samples (4 ml) will be collected at 0.5, 1, 2, 4, 8- and 24-hourspost-dose per Schedule of Events (Table 24).

For each subject, up to 6 blood samples (24 mL of blood) will becollected during the study for PK analysis. In addition, approximately15 mL of blood will be collected at screening, approximately 15 mL ofblood will be collected at Day 3 Discharge, and approximately 15 mL ofblood will be collected at Day 7(+2) for clinical laboratory testing.The total volume of blood collected during the study is expected to beapproximately 69 mL.

For re-dosed subjects only: an extra PK blood sample (4 ml) will becollected at 2.5 hours post first dose in addition to the other times,totaling approximately 73 ml. All PK sampling will occur only after theall other assessments at that time point are conducted.

Pharmacokinetic Analyses

All pharmacokinetic parameters will be calculated usingnon-compartmental analysis using WinNonlin. Actual sampling times willbe used in all pharmacokinetic analyses. Per protocol times will be usedto calculate mean plasma concentrations for graphical displays. Other PKanalyses may be performed as appropriate.

EXAMPLE 5: A PHASE IB/II, MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBOCONTROLLED, ASCENDING DOSE FINDING, EFFICACY, PHARMACOKINETIC AND SAFETYSTUDY OF DEXMEDETOMIDINE HYDROCHLORIDE SUBLINGUAL FILM TO TREAT SYMPTOMSOF ACUTE OPIOID WITHDRAWAL IN PATIENTS WITH OPIOID USE DISORDER WHO AREPHYSICALLY DEPENDENT ON OPIOIDS

Primary Objective:

Establish the safety and tolerability of ascending doses ofdexmedetomidine hydrochloride sublingual film relative to placebo insubjects with opioid use disorder who are physically dependent onopioids and maintained on oral morphine.

Secondary Objectives:

Establish the efficacy of dexmedetomidine hydrochloride sublingual filmrelative to placebo in improving the following:

-   -   1. Opioid withdrawal symptoms:    -   Short Opiate Withdrawal Scale of Gossop (SOWS-GOS SOP) and    -   Clinical Opiate Withdrawal Scale (COWS)    -   2. Time to dropout after opioid discontinuation    -   3. Percentage of subjects dropping out after opioid        discontinuation    -   4. Assessment of safety reflected by scores on the Agitation and        Calmness Evaluation Scale (ACES) assessment

Exploratory Objective:

Evaluation of pharmacokinetics in subjects undergoing opiate withdrawal.

Study Design: This inpatient Phase Ib study will assess the safety,pharmacokinetics, and early signs of efficacy of escalating doses ofdexmedetomidine hydrochloride sublingual film versus placebo followingdiscontinuation of morphine maintenance. The opioid maintenance phasewill be occurring during Study Days 1-5; the randomized dexmedetomidinehydrochloride sublingual film/placebo phase will occur on Study Days6-12. This will be followed by 2 days of placebo sublingual film (fordexmedetomidine) and morphine-placebo treatment for all remainingsubjects on days 13-14.

After a 30-day screening period, eligible male and female adult subjectswith OUD who are physically dependent on opioids will be admitted to aninpatient unit. At the start of the opioid maintenance phase (Study Days1-5), subjects (n=125 enrollers) will receive oral morphine (30 mg) fourtimes a day (QID) approximately every 6 hours or up to 5 times per dayas needed. The total dose of morphine during the first two days ofstabilization (Study Days 1-2) can vary at the discretion of theinvestigator, between 120 mg and 150 mg per day depending on patientsabuse history and need for higher dose to stabilize withdrawal symptoms.During the next three days (Study Days 3-5), all subjects will receive astandard dose of morphine (30 mg QID) totaling 120 mg in a day. Inaddition, all subjects will receive placebo films, approximately 12hours apart during this opioid maintenance phase (i.e., Days 1-5) tosimulate and thus blind treatment with dexmedetomidine sublingual filmduring Days 6-12.

Starting on the morning of Day 6, blinded abrupt discontinuation ofactive morphine will begin by replacing active morphine with placebomorphine. Placebo morphine capsules will be identical in appearance tothe morphine capsules taken during the opioid maintenance period. Onthis day (Study Day 6), subjects will be randomized (within each cohort,20 subjects will receive active dexmedetomidine sublingual film and 5subjects will receive placebo) to receive either placebo ordexmedetomidine hydrochloride films administered twice a day (BID),approximately 12 hours apart at approximately 8 am and 8 pm. Placebosublingual film or dexmedetomidine sublingual film will be administeredon Days 6-12. On days 13 and 14, all remaining subjects will receiveplacebo morphine capsules (QID) and placebo sublingual films (BID).

It is anticipated that a total of 5 cohorts will be tested (n=25 percohort) with potential to add cohorts or select different doses/scheduleof dosing based on ongoing safety review and medical monitoring. Thefollowing doses will be administered: 30 μg (Cohort 1), 60 μg (Cohort2), 90 μg (Cohort 3), 120 μg (Cohort 4), and 180 μg (Cohort 5). Safetyand tolerability will be monitored continuously and summarized uponcompletion of each cohort by medical safety review. Studies of opioidwithdrawal with placebo arms are likely to have high dropout rates,thus, the dropouts prior to Day 6 may be replaced to ensure enoughsample size entering the treatment phase. The study is intended to beflexible and adaptable and as such, the dosing frequency, the doses andthe number of cohorts of dexmedetomidine hydrochloride sublingual filmmay be changed as a result of review of safety, tolerability andefficacy data.

Opioid withdrawal symptoms (SOWS-Gossop and COWS) will be measuredthroughout the inpatient period at Predose, 2 hours post dose, pre 2nddose and 2 hours post second dose. Additional/SOWS-Gossop/COWS may beadministered at investigator discretion. Transition to treatment foropioid use disorder will be offered prior to patients leaving the unit.

Vital Signs, SOWS-Gossop, COWS, pulse oximetry and electrocardiogram(ECG) with rhythm strip will be measured as per the schedule ofassessments(Table 25. Dexmedetomidine sublingual film or placebo will beself-administered sublingually under staff observation and subjects willbe allowed fluids as desired 15 minutes after completion of dosing.Safety and tolerability assessments will be continued until the morningof Day 14 (day of discharge).

Any abnormal vital sign measurement, clinical laboratory test, physicalexamination finding, or ECG parameter deemed clinically significant bythe investigator will be repeated, including test results obtained onthe final study day or upon early termination. For any test abnormalitydeemed clinically significant, repeat analysis will be performed duringthe follow-up period and until the value returns to baseline (or withinnormal limits) or the investigator deems the abnormality to be stableand no longer of clinical concern.

Diagnosis and Main Criteria for Eligibility:

Inclusion Criteria

-   -   1. Male and female subjects who are 18 years of age to less than        65 years of age.    -   2. Meets criteria for moderate to severe opioid use disorder as        per Diagnostic and Statistical Manual of Mental Disorders, Fifth        Edition (DSM-5) criteria and confirmed by the Mini-International        Neuropsychiatric Interview (MINI) with physiological dependence        as evidenced by a Clinical Opiate Withdrawal (COWS) score of >5        or a positive naloxone challenge upon admission on Day 1.    -   3. Subjects who can read, understand and provide written        informed consent.    -   4. Women of childbearing potential must have a negative        pregnancy test and agree to be abstinent or use an acceptable        method of contraception for the duration of the study.

Exclusion Criteria

-   -   1. Positive urine pregnancy test at screening or when tested or        currently breast feeding.    -   2. Clinically significant history of cardiac disease, screening        and baseline heart rate of <55 beats per minutes or systolic        blood pressure <110 mmHg or diastolic blood pressure <70 mmHg.    -   3. History or presence of a significant medical disease or        disorder which, in the opinion of the investigator, increases        the risk or may confound the interpretation of study measures,        as confirmed by screening laboratory results.    -   4. Hepatic dysfunction (marked by ascites, or bilirubin >10%        above the upper limit of normal [ULN] or liver function        tests >3×ULN) at the screening visit.    -   5. Acute active Hepatitis B or C as evidenced by positive        serology and aspartate aminotransferase (AST)/alanine        aminotransferase (ALT)>2×ULN.    -   6. Clinically significant abnormal ECG findings such as second        or third degree heart block, uncontrolled arrhythmia, or QTc        interval >450 msec for males, and >470 msec for females at        screening or prior to dosing.    -   7. Any psychiatric disorder that would compromise ability to        complete study requirements.    -   8. Currently meets DSM-5 criteria for substance abuse disorder,        moderate or severe for any substance other than opioids,        caffeine, or nicotine.    -   9. History of suicidal behavior within the last 1 year prior to        screening.    -   10. Participation in a clinical trial of a non-FDA-approved        pharmacological agent within 30 days prior to screening.    -   11. Use of any excluded medication at screening or        anticipated/required use during the study period.    -   12. Subjects with a history of intolerance to morphine.    -   13. Any finding that, in the view of the principal investigator,        would compromise the subject's ability to fulfill the protocol        visit schedule or visit requirements.

Study Treatments

Test Product, Dose, and Mode of Administration:

Dexmedetomidine hydrochloride sublingual film 30 μg, 60 μg, 90 μg, 120μg and 180 μg doses as a thin film formulation of Dexmedetomidine forsublingual (SL) administration. The product is a small, solid-dose filmformulation designed to completely dissolve in the SL space within 1-3minutes.

Reference Therapy, Dosage and Mode of Administration:

Matching placebo films to be taken sublingually as described above.

Duration of Treatment:

30 mg QID or 5×/day Morphine and placebo sublingual film (ofdexmedetomidine): 5 days; BID dexmedetomidine hydrochloride sublingualfilm or placebo sublingual film and morphine placebo: 7 days, placebosublingual film (of dexmedetomidine) and morphine placebo: 2 days.

Study Procedures

Subjects will provide written informed consent before any study-relatedprocedures are initiated, including the cessation of prohibitedconcomitant therapy.

TABLE 25 Schedule of Visits and Assessments Inpatient Admission (14days) Detoxification Randomization & Post Morphine first day ofTreatment Treatment One-week Screening¹ maintenance treatment Phasephase or ET Follow-up −2 Days Day Days Days Day 21 Day to −1 1-5 6 7-1213-14 (±3 days) Naloxone X Administration² Informed Consent XInclusion/Exclusion X X Criteria³ Mini International X NeuropsychiatricInventory (MINI) Columbia Suicide X Severity Rating Scale (C-SSRS)Randomization (Day 6) X Demographics X Medical and Psychiatric X HistoryConcomitant X X X X X X Medications Physical Exam and X X X X X 12-LeadECG⁴ Safety tabs X X X Vital Signs X X X X X X Measurements⁵ Buccal SL XX X X assessment⁶ Rapid Urine X X Pregnancy Testing⁷ AE Monitoring X X XX X X Urine Toxicology/BAL⁸ X X X X X Timeline Followback X XPharmacokinetics⁹ X  X¹⁰ SOWS & COWS¹¹ X X X X X Administration X ofMorphine Administration of X X Dexmedetomidine sublingual film orPlacebo¹² Administration of X X Morphine Placebo¹³ Administration of Xsublingual film placebo (for dex) and morphine placebo Agitation andCalmness X X X Evaluation Scale (ACES)¹⁴ Notes: ¹All procedures must becompleted prior to subject randomization and within 30 days of signinginformed consent. ²Subjects have the option of naloxone challenge onadmission if not displaying signs/symptoms of withdrawal. If naloxone isadministered, subjects may receive morphine to alleviate the opioidwithdrawal symptoms that may be present at the end of the challengetest. ³Inclusion/Exclusion criteria evaluated at Screening and pre doseon Randomization Day 6. ⁴ECG will be done on Screening, pre-morning doseof sublingual film-placebo (of dex) on Day 1-5, pre-dose on Day 6, andon Days 13-14. ⁵Vital sign measurements will include orthostatic bloodpressure, pulse, and measurement of oxygen saturation. Vitals will betaken on days 1-5 once daily, and pre each dose on days 6-12, and oncedaily on days 13 and 14. ⁶Buccal exam at 30 min post first dose forsigns of local irritation on Days 1, 6, & 12. Buccal exam will be doneprior to discharge on Day 14. Additional buccal exam may be done atinvestigator's discretion or in case of a relevant adverse event.⁷During screening, a rapid urine pregnancy test will be performed. Aspart of inpatient admission, a rapid urine pregnancy test will beperformed on Study Day 1. ⁸Urine drug testing will include opioids(fentanyl), buprenorphine, methadone, , benzodiazepines, cocaine(benzoylecgonine), amphetamines, and other drugs. Breath alcohol levels(BAL) will be assessed at screening, Day 1 and follow-up. ⁹Blood samplesfor pharmacokinetic analyses will only take place on inpatient StudyDays 6 and 12 at 0, 2, , 6, and 12 hr after the first dose ofDexmedetomidine sublingual film of the day. The 12 hr. sample will betaken just before the administration of the next dose of Dexmedetomidinesublingual film or placebo sublingual film (for dexmedetomidine). Awindow of +/−5 mins per PK sample will be allowed without deviation.¹⁰PK samples will be collected on Day 12 only at the scheduled times.¹¹COWS and SOWS-Gossop assessments will be performed Pre-dose, 2 hourpost-dose, pre-2^(nd) dose, and 2 hour post 2^(nd) dose. Additionalassessments can be done at investigator's discretion. ¹²Administrationof Dexmedetomidine sublingual film or Placebo will be given BID(approximately 8 am and 8 pm [+/−30 minutes]). On Days 1-5, subjectswill receive placebo sublingual films (of dex) approximately 12 hoursapart, besides their morphine treatments. ¹³Morphine placebo will beadministered at approximate same time as Day 1-5. ¹⁴Administration ofthe Agitation and Calmness Evaluation Scale (ACES) will occur atapproximately two hours after (−5/+15 mins) Dexmedetomidine sublingualfilm or placebo dosing (approximately 10 am and 10 pm).

Criteria for Evaluation:

Efficacy assessment: Determine the preliminary efficacy of sublingualdosing of dexmedetomidine hydrochloride sublingual film in the targetpopulation compared to placebo, as measured by improved peak SOWS-Gossopscores.

The effect of study drug will be evaluated using several validatedinstruments as described below.

Short Opiate Withdrawal Scale of Gossop (Also-Gossop)

The SOWS-Gossop is a 10-item patient reported measure designed tomeasure the symptoms of withdrawal in subjects who are dependent onopioids (Gossop, 1990). Each of the 10 items represents a symptom:“Feeling Sick,” “Stomach Cramps,” “Muscle Spasms/Twitching,” “Feeling ofColdness,” “Heart Pounding,” “Muscular Tension,” “Aches and Pains,”“Yawning,” “Runny Eyes,” and “Insomnia/Problems Sleeping.” Subjectsevaluate the severity of each symptom over the last 24 hours byselecting either as “None,” “Mild,” “Moderate,” or “Severe.”

The SOWS-Gossop total score range from 0 to 30, with higher scoresindicating greater severity of withdrawal symptoms.

Clinical Opiate Withdrawal Scale

The COWS is an 11-item questionnaire designed to measure a patient'slevel of opiate withdrawal (Wesson and Ling, 2003). Symptoms evaluatedinclude resting pulse rate, sweating, restlessness, pupil size, bone orjoint aches, runny nose or tearing, gastrointestinal upset, tremor,yawning, anxiety or irritability, and gooseflesh. COWS total scoresrange from 0 to 48; scores 5 to 12 are mild, 13 to 24 are moderate, 25to 36 are moderately severe, and over 36 are severe withdrawal

Safety and Tolerability Assessments:

COWS, SOWS-Gossop, adverse events (AEs), clinical laboratory tests, ECGwith rhythm strip, pulse oximetry and vital signs will be monitored fortolerability assessment. The ACES assessment will also be administeredas a safety measure. All observed and volunteered AEs will be recorded.The relationship of AEs to the study drugs will be graded as notrelated, unlikely/remotely related, possibly related, probably relatedor definitely related by the investigators. Vital signs includingsystolic blood pressure (SBP), diastolic blood pressure (DBP),orthostatic blood pressure, heart rate, and oxygen saturation will bemeasured daily throughout the study. The application site of the SLpreparation (buccal mucosa) will be inspected for any signs of localirritation.

Additional Assessments:

-   -   Demographic Data    -   Medical and Psychiatric History    -   Prior and Concomitant Medication    -   Physical Examination    -   Suicidality    -   Pregnancy

Pharmacokinetics

Blood samples (4 ml) will be collected at 0, 2, 6, and 12 hours afterthe first dose of dexmedetomidine hydrochloride sublingual film on StudyDays 6 and 12. The 12 hr. sample will be taken just before theadministration of the next dose of dexmedetomidine sublingual film orplacebo.

Statistical Analysis:

Primary Outcome: Safety and tolerability of ascending doses ofdexmedetomidine hydrochloride sublingual film in subjects with OUD whoare physically dependent on opioids.

Secondary Outcomes:

-   -   1) Peak SOWS-Gossop score during Days 6-14.    -   2) Peak COWS score during Days 6-14    -   3) Average COWS scores per day for Days 6-14 (an average will be        calculated for each day in order to assess time course of        withdrawal symptoms).    -   4) Average SOWS-Gossop scores per day on Days 6-14.    -   5) Time to dropout after discontinuation of morphine maintenance        (Days 6-14).    -   6) Percentage of subjects dropping out after discontinuation of        opioid maintenance within each treatment group between Days 6-14    -   7) Overall agitation and sedation will be evaluated with the        ACES.

Efficacy Analyses

Primary: After the morphine maintenance phase, treatment differencesbetween dexmedetomidine hydrochloride sublingual film and placebo onpeak SOWS-Gossop scores on Days 6-14 will be analyzed using linearregression or Mixed Model Repeated Measures [MMRM]. Treatmentdifferences between dexmedetomidine sublingual film and placebo on peakSOWS scores on Day 7 (two days after opiate discontinuation) as well aspeak SOWS on Days 6 14 will be analyzed. The intent-to-treat populationwill be analyzed and consist of all patients who take any studymedication and who had both baseline and at least 1 efficacy assessmentafter dosing.

Secondary: Peak COWS scores during Days 6-14 will each be comparedbetween the dexmedetomidine hydrochloride sublingual film and placebogroups using linear regression or MMRM. Time to dropout afterdiscontinuation of morphine maintenance will be analyzed using a Coxproportional-hazards model. Kaplan-Meier estimates will also be used togenerate survival curves over time in each treatment group. Logisticregression model will be used to compare the dexmedetomidinehydrochloride sublingual film and placebo groups on the numbers ofsubjects dropping out after opioid discontinuation. Listings of subjectswho withdraw from the study due to an AE, serious AEs and/or death orlack of treatment effect will be presented. Laboratory parameters willbe summarized by treatment using descriptive statistics and datalistings of clinically significant abnormalities. Vital signs and ECGdata will be summarized by changes from baseline values usingdescriptive statistics. Chi-square (or Fisher's exact) tests will beused to compare the frequencies of AEs or serious AEs on blood pressure,heart rate, or respiratory drive between dexmedetomidine hydrochloridesublingual film and placebo, at the beginning of Day 6 and then dailyduring the remainder of this study.

Pharmacokinetic Analyses

A separate SAP for the PK analyses will be prepared for the study andwill be finalized prior to database lock. Data from subjects whoparticipated in the study will be included in the pharmacokineticanalysis. Subjects with missing sample concentrations will be includedin the pharmacokinetic analyses provided their pharmacokineticparameters can be adequately characterized based upon the remainingdata.

Safety Analyses

Safety data analyses will be conducted on all subjects receiving atleast 1 dose of study drug. The number and percentage of subjectsexperiencing 1 or more AEs will be summarized by treatment, relationshipto study drug, and severity. AEs will be coded using Medical Dictionaryfor Regulatory Activities (MedDRA) terminology.

EXAMPLE 6: A PHASE IB/II RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED,DOSE FINDING, EFFICACY AND SAFETY STUDY OF DEXMEDETOMIDINE HYDROCHLORIDESUBLINGUAL FILM TO TREAT PATIENTS HOSPITALIZED IN THE ICU WITH DELIRIUMAND AGITATION

Key Objectives:

-   -   1. To assess the impact of dexmedetomidine sublingual film on        cardiovascular parameters, including blood pressure, heart rate,        and QTc interval, in hospitalized patients with hyperactive        delirium.    -   2. To assess the incidence of other side effects following the        administration of dexmedetomidine sublingual film in the same        patient group.    -   3. To explore the impact of dexmedetomidine sublingual film on        agitation and delirium severity    -   4. To identify the optimal dose of dexmedetomidine that is        effective at reducing agitation and delirium severity without        causing significant side effects.

Inclusion/Exclusion Criteria

Inclusion Criteria:

-   -   1. Adults hospitalized on a medical or surgical intensive care        unit at MGH    -   2. Diagnosis of delirium, assessed according to DSM-5 criteria        (DSM-5) by a licensed psychiatrist    -   3. Body mass index (BMI) between 18 and 30 kg/m², inclusive, at        screening    -   4. Weight at least 60 kg (132 pounds), at screening    -   5. Sufficiently physically healthy in the opinion of the study        and clinical teams to receive dexmedetomidine sublingual film

Exclusion Criteria:

-   -   1. Per medical record or team report, diagnoses of:        -   Dementia        -   Significant traumatic brain injury        -   History of stroke, with persistent neurologic deficits    -   2. Presence of any of the following cardiovascular comorbidities        -   Sick sinus syndrome        -   A resting heart rate of <55 beats per minutes or systolic            blood pressure <100 mmHg or >160 mmHg or diastolic BP<70            mmHg or >95 mmHg at enrollment and prior to dosing.        -   Evidence of cardiac ischemia on a 12-lead electrocardiogram            (ECG)        -   Corrected QT interval of >450 msec        -   Presence of a permanent pacemaker device    -   3. Per medical record (notes, current medications, flowsheets):        -   Second degree (or greater) AV block without a pacemaker        -   Known allergy or adverse reaction to dexmedetomidine        -   Current use of dexmedetomidine    -   4. Inability to take sublingual dexmedetomidine due to severe        agitation, neurological impairment, NPO status, or other cause.    -   5. Hepatic impairment (liver function tests >3 times the upper        limit of normal)    -   6. Severe renal impairment (GFR <30 ml/min or on dialysis)    -   7. Weight <60 kg    -   8. Pregnancy (in women; tested with serum or urine hCG)    -   9. Non-fluency in English    -   10. Prior enrollment in the study, with receipt of study        medication, during the current or a previous hospitalization

Assessment for Inclusion Criteria:

Inclusion and exclusion criteria will be assessed in a stepwise fashion.Prior to approaching participants/surrogates, study staff will reviewthe electronic medical record to assess for exclusionary conditions andwill discuss with clinical teams if the presence or absence of suchconditions is unclear. Only those patients who do not clearly meetexclusion criteria will be evaluated further for inclusion and exclusioncriteria by the study psychiatrist.

Specifically, the study psychiatrist will confirm a diagnosis ofdelirium through review of the medical record, evaluation of thepotential participant, and discussion with the inpatient team if anyquestions about diagnosis remain following the evaluation. Delirium willbe diagnosed using DSM-5 criteria:

-   -   1.) There is a disturbance in attention and awareness.    -   2.) The disturbance develops over a short period of time,        represents an acute change from baseline, and tends to fluctuate        over the course of the day.    -   3.) There is an additional disturbance in cognition.    -   4.) The disturbances are not better explained by an underlying        neurocognitive disorder (e.g., dementia).    -   5.) The disturbances do not occur in the context of a severely        reduced level of arousal (e.g., coma).    -   6.) There is evidence that the disturbance is a direct        physiological consequence of another medical condition,        substance intoxication or withdrawal, or exposure to a toxin, or        is due to multiple etiologies.

This clinical diagnosis will be made in the context of a psychiatric andcognitive evaluation, including bedside tests of orientation, attention,and memory.

If a patient meets criteria for delirium, the study psychiatrist willthen review the patient's medical record further and speak with theinpatient team to determine if any exclusion criteria are present. Toensure the clinical team feels that the participant is medically able totolerate dexmedetomidine, they will be asked whether they would considerthe participant to be suitable to receive dexmedetomidine intravenouslyif he/she were to become agitated. If participants meet diagnosticcriteria for delirium and do not meet any exclusion criteria, they willbe considered eligible for inclusion in the study.

Following enrollment in the study, laboratory testing and obtainment ofan ECG will be performed to confirm clinical stability prior tomedication administration. If a participant is experiencing agitationimmediately following enrollment and confirmation of clinical stability,the participant will be eligible to be randomized to receive the studymedication. If the participant does not have evidence of agitation, theparticipant will be monitored on a daily basis for the development ofagitation (RASS≥1) and will be randomized only if/once agitation hasdeveloped. While patients with or without agitation will be eligible forenrollment in the study, only those participants who become agitatedwill receive dexmedetomidine film.

Study Procedures

A. Data Collection and Monitoring

Initial screening and data collection. As noted, prior to enrollment,study psychiatrists will assess the patient for inclusion and exclusioncriteria via brief medical record review, discussion with primarytreatment team, diagnostic evaluation (DSM-5 criteria), and assessmentfor decision-making capacity. For enrolled subjects, chart reviews willbe performed to gather baseline characteristics (Table 26—schedule ofevents).

Further screening for eligibility to receive study medication. Followingenrollment, laboratory studies, including comprehensive metabolic panel(glucose, sodium, potassium, chloride, bicarbonate, calcium, carbondioxide, magnesium, blood urea nitrogen, creatinine, uric acid,inorganic phosphorus) and liver function tests (alkaline phosphatase,aspartate aminotransferase [AST], alanine aminotransferase [ALT],gamma-glutamyl transferase, total bilirubin) will be performed.

Additionally, serum human chorionic gonadotropin (HCG; femaleparticipants only) will be obtained. If these laboratory studies werealready drawn during this admission, new samples will not be drawnunless a change in clinical status that might affect them has occurred.Finally, a standard, 12-lead ECG will be obtained. The ECG parametersassessed will include heart rate and PR, QRS, QT, and QTc using Bazett's(QTcB) and Fridericia's (QTcF) correction methods. The QTcF will beconsidered the standard QTc interval to evaluate any changes in QTc inresponse to the study medication. The ECGs will be interpreted by theinvestigator, and if needed in the medical opinion of the principalinvestigator or designee, the findings will be confirmed by acardiologist, critical care physician, or anesthesiologist. Studymedication administration will not occur until all necessary laboratorystudies have resulted and the participant's eligibility for medicationadministration has been confirmed.

Monitoring for the development of agitation: On a daily basis during thework week, the participant will be evaluated by a study team memberusing the Richmond Agitation Sedation Scale (RASS). If/when aparticipant is found to have significant agitation (defined as a RASSscore 1), the participant will undergo baseline monitoring proceduresand will be randomized to one of the two treatment conditions.

Randomization: Participants will be randomized to receive either 20 μgor 60 μg of dexmedetomidine sublingually. As dexmedetomidine isavailable in 10 and 60 μg films, those receiving 20 μg will receive two10 μg films, while those receiving 60 μg will receive a 60 μg film and aplacebo film to ensure blinding of staff and participants. Participantswill receive repeat dosing every 30 minutes for up to three additionaldoses, leading to maximum doses of 80 μg and 240 μg, respectively. Bothinvestigators and clinicians will be blind to the participant's group,with only the study pharmacist aware of the dose of medication on thefilms.

Baseline monitoring. Following enrollment, the study team will recordbaseline measures of heart rate, blood pressure, and oxygen saturation.An ECG will be performed and QTcF measured. Next, the physician willevaluate the patient using the RASS and DRS-R-98 to measure baselineagitation and delirium severity, respectively.

Medication administration. Dexmedetomidine sublingual film will beadministered by the study physician or study nurse as per themanufacturer's instructions. Specifically, the film will be placed intothe participant's mouth. The participants will be instructed to keep thefilm in their mouth until it dissolves. If the participant is unable tohold the medication in their mouth (e.g., they spit it out), theparticipant will not be re-dosed. Dexmedetomidine administration will berepeated every 30 minutes if the participant continues to have agitation(RASS and does not meet any cardiovascular stopping criteria. Dosingtimes and maximum medication doses are as follows in table 27:

TABLE 27 Dosing times and maximum medication doses Administration Time(minutes) Group 0 30 60 90 Total Dose 20 μg 20 μg 20 μg 20 μg 20 μg  80μg 60 μg 60 μg 60 μg 60 μg 60 μg 240 μg

Monitoring for side effects. Heart rate, blood pressure, oxygensaturation, use of supplemental oxygen, and use of pressors will bemonitored continuously and recorded every 30 minutes from theparticipant's Epic flowsheet or using the telemetry monitor/automatedblood pressure cuff for the 6 hours following the initial medicationadministration (baseline; Time 0). An ECG will be performed at 1.5, 3,4.5, and 6 hours, and QTc will be calculated using the Fridericiaformula, as described above. Study staff will also monitor theparticipant and speak with nursing staff at 6 hours to assess for anyother side effects/complaints the patient may have had during the timesince medication administration. These will be assessed formally using alist of side effects reported for dexmedetomidine in post-marketingsurveillance.

Monitoring of agitation and delirium severity. The RASS will beperformed every 30 minutes (up to 6 hours post-baseline) by study staff(research coordinator, nurse, or study psychiatrist) to monitor foragitation. The DRS-R-98 will be performed by the study physician at 1,2, 3, 4, and 6 hours post-baseline to assess for changes in deliriumseverity. If patients require additional treatments to manage agitationfollowing medication administration within the 6-hour monitoring period,all efficacy and safety assessments from that point forward willcontinue, but those time points for those patients will not be analyzedin the primary data analysis.

Dosing will be stopped at any time if any of the following occurs:

-   -   1) There is >30 mm Hg decrease in systolic or diastolic blood        pressure.    -   2) There is an isolated drop in Systolic BP<95 mmHg.    -   3) There is an isolated drop Diastolic BP<55 mmHg.    -   4) There is a decrease in heart rate of 20 beats per minute or a        drop below 55 beats per minute.    -   5) ECG reveals QTc >500 msec.    -   6) Attainment of a RASS of −1.

TABLE 26 Schedule of study events. Pre- Med 30 1 1.5 2 2.5 3 3.5 4 4.5 6Measure enrollment Baseline Admin. min h h h h h h h h h Delirium XScreening (CAM-ICU) Delirium X Diagnosis (DSM-5) Agitation X X X X X X XX X X X X X (RASS) Delirium X X X X X X Severity (DSR-R-98) Heart X X XX X X X X X X X X Rate Blood X X X X X X X X X X X X Pressure Oxygen X XX X X X X X X X X X Saturation Electrocardiogram X X X X X Other side Xeffects

Study Drugs:

In this study, we will administer the medication in sublingual filmformulation (absorbed sublingually) at a dose of 20 or 60 μg (withrepeated administration, participants may receive a total of up to 80 μgor 240 μg, respectively).

Data Collection

Baseline data. Prior to administration of dexmedetomidine, the studyphysician will perform the RASS and DRS-R-98 to assess level ofagitation and delirium severity. Heart rate, blood pressure, and oxygensaturation will be recorded from the participant's telemetry monitor andusing an automated blood pressure cuff. Finally, an ECG will beperformed, and the study physician will calculate a QTc interval.

Cardiovascular parameters and side effects. Following administration ofdexmedetomidine, heart rate, blood pressure and oxygen saturation willbe recorded every 30 minutes from the telemetry monitor or Epicflowsheet. Consistent with prior research, we will monitor for thefollowing side effects:

-   -   (a) Bradycardia—heart rate <55 beats per minute (or ≥20%        reduction in heart rate from baseline if baseline heart rate is        <70 beats per minute)    -   (b) Hypotension—systolic blood pressure <95 mmHg (or ≥20%        decrease in systolic blood pressure from baseline if baseline        systolic blood pressure is <120 mm Hg), or the addition or        increase of vasopressors    -   (c) Tachycardia—heart rate >100 beats per minute (or ≥20%        increase in heart rate from baseline if baseline heart rate        is >83 beats per minute)    -   (d) Hypertension—systolic blood pressure >160 mmHg (or ≥20%        increase in systolic blood pressure from baseline if baseline        systolic blood pressure is >133 mm Hg)    -   (e) Hypoxia—oxygen saturation <90% (or ≥5% decrease in absolute        value of oxygen saturation if baseline oxygen saturation is less        than 95%), or increase in the amount of supplemental oxygen        required to maintain oxygen saturation >90%    -   (f) ECG changes (including QTc prolongation)—The ECG parameters        will include heart rate, PR interval, QRS interval, QT interval,        and QTc interval (rate correction using QTcB and QTcF methods).        Summaries of ECG results and the change from baseline will be        presented. The numbers and percentages of participants with a        QTc increase from baseline to 90-minute ECG time point will be        summarized using the following change categories:        -   a. QTc interval increase from baseline >30 to <60 msec        -   b. QTc interval increase from baseline >60 msec    -   In addition, QTc values will be summarized by gender as normal        to prolonged in accordance with Committee for Proprietary        Medicinal Products (CPMP) Points to Consider regarding the        assessment of the potential for QT interval prolongation shown        in the Table 28:

TABLE 28 QTcF Intervals: Upper and Lower Limits of Normal, Borderline,and Prolonged Intervals Males Females Normal ≤430 msec ≤450 msecBorderline >430 to ≤450 msec >450 to ≤470 msec Prolonged >450 msec >470msec Note: In accordance with CPMP guidelines.

Similarly, the numbers and percentages of participants with absolute QTcinterval values above certain thresholds will be summarized by genderusing the following limits in accordance with International Conferenceon Harmonisation (ICH) E14 guidance:

-   -   QTc interval >450 to ≤480 msec    -   QTc interval >480 msec    -   QTc interval ≥500 msec

A listing of participants with QTc change from baseline between 30 to 60msec and ≥60 msec will be provided. A listing of participants withabnormal QTc interval values (>450 msec to <500 msec and ≥500 msec) willbe provided to the Sponsor as well.

Non-cardiovascular side effects. During the final assessment (6 hoursafter the initial dose of the medication), participants will be askedthe following question: “Have you noticed any new physical problems orside effects since receiving the study medication?” In addition, theparticipant's primary nurse will be asked whether the patient had signsor symptoms of new medical conditions or side effects (e.g., musclestiffness, tremor, rash) since the administration of the medication,using a checklist of side effects reported in post-marketingsurveillance.

Impact on agitation and delirium severity.

(a) Agitation: Agitation will be measured using the RASS, a 10-pointscale to quantify levels of consciousness and agitation. This validatedmeasure can be administered in less than one minute and has cleardefinitions for levels of arousal/agitation. The RASS will beadministered at baseline and every 30 minutes (up to 6 hourspost-baseline) by a research coordinator, study nurse, or studypsychiatrist.

(b) Delirium severity: The DRS-R-98 will be used as a measure ofdelirium severity. This 16-item scale can be used to screen for/diagnosedelirium, but it also includes 13 items to assess delirium severity. Itis reliable and has been validated in patients with delirium. This scalewill be administered by a study physician at baseline, then 1, 2, 3, 4,and 6 hours after the initial dexmedetomidine administration.

EXAMPLE 7: PHASE 1, RANDOMIZED, SINGLE-BLIND, PLACEBO-CONTROLLED, SINGLEASCENDING DOSE STUDY OF THE PHARMACOKINETICS, SAFETY & TOLERABILITY OFDEXMEDETOMIDINE SUBLINGUAL FILM (EXAMPLE 1 FORMULATION) IN HEALTHY ADULTVOLUNTEERS

This was a randomized, single-blind, placebo-controlled, singleascending dose pharmacokinetics, safety and tolerability study with 4dosing groups in healthy adult (18-65 years-old) males and females. Thestudy protocol was reviewed and approved by an institutional reviewboard of site(s). This study was conducted in accordance with theDeclaration of Helsinki and ICH-Good Clinical Practices (GCP).

Primary Objective: Determine the PK, safety and tolerability of thevarious film strengths of dexmedetomidine sublingual film foridentification of appropriate film dosage strengths to be carriedforward into subsequent clinical trials.

Secondary Objectives:

-   -   1. Determine the PD effects of the various film strengths of        dexmedetomidine sublingual film.    -   2. Determine the relationship between PD effects and plasma        concentrations of the dexmedetomidine.    -   3. Determine the time to onset of drowsiness after        dexmedetomidine sublingual film administration.    -   4. Determine the length of sedative effect after dexmedetomidine        sublingual film administration.    -   5. Determine the approximate dissolution time of dexmedetomidine        sublingual films in the SL space.    -   6. Determine local irritation that may be caused by        dexmedetomidine sublingual film.

Endpoints

Primary

Pharmacokinetics

-   -   1. Area under the curve (AUC0-12, AUC0-24, AUC0-inf) for 0 to 12        hours and 0 to 24 hours post dosing for dexmedetomidine plasma        concentration.    -   2. Determine peak plasma dexmedetomidine concentration (Cmax).    -   3. Determine time corresponding to peak dexmedetomidine        concentration level (Tmax).    -   4. Determine terminal half-life (t1/2) of dexmedetomidine from        the central compartment.    -   5. Determine the volume of distribution (Vz) of dexmedetomidine.    -   6. Determine the clearance of dexmedetomidine (CL) from the        central compartment.

Safety and Tolerability

-   -   1. Determine electrocardiogram (ECG) and vital sign        abnormalities including adverse effects on blood pressure (BP),        heart rate, or respirations with various film strengths of        dexmedetomidine sublingual film.    -   2. Determine abnormal laboratory values following administration        of dexmedetomidine sublingual film.    -   3. Determine changes in physical examination following        administration of dexmedetomidine sublingual film    -   4. Number of subjects experiencing an AE up to Day 14 following        dexmedetomidine sublingual film administration.    -   5. Number of subjects who discontinued study treatment or        removed SL films due to an AE or other reason.    -   6. The degree to which AEs can be tolerated by assessing the        number of subjects requiring:        -   Hemodynamic interventions for maintaining BP;        -   Cardiac interventions for maintaining heart rate;    -   Respiratory interventions for maintaining oxygen saturation.

Secondary

-   -   1. The sedative effect assessed by RASS and Visual analogue        scales/sedation (VAS/S) on day of dexmedetomidine sublingual        film dosing.    -   2. Time in minutes and seconds from administration of        dexmedetomidine sublingual film until RASS of −1 on day of        dexmedetomidine sublingual film dosing.    -   3. Time in minutes and seconds from RASS of −1 till resolution        of drowsiness on day of dexmedetomidine sublingual film dosing.    -   4. Time in minutes and seconds from SL administration of        dexmedetomidine sublingual film till its complete dissolution or        up to 30 minutes.

Study design: It was a randomized, single-blind, placebo controlled,single ascending dose PK, safety and tolerability study conducted inhealthy adult (18-65-year-old) males and females. The study evaluatedincreasing doses of dexmedetomidine sublingual film in 4 cohorts ofhealthy adult participants.

Four (4) doses were evaluated derived from three film strengths of 10μg, 40 μg, and 60 μg: 10 μg, 20 μg (2×10 μg film), 40 μg, and 60 μg inCohort 1, 2, 3 and 4 respectively. During the review of the safety andtolerability data from Cohort 3 dosing (40 μg), it was observed that 6symptomatic subjects had reported dizziness upon standing, four of whomhad concomitant intermittent hypotension or bradycardia (SBP/DBP/heartrate with >30 mmHg decrease from baseline, SBP <90 or DBP <60 or heartrate <50). While the results remained blinded, it was decided todecrease the planned dose for Cohort 4 to 40 μg. The actual dosesadministered to subjects in this study included 10 μg (cohort 1), 20 μg(cohort 2) and 40 μg (cohorts 3 and 4).

All eligible participants, who have been previously screened, arrived atthe clinical research unit (CRU) a day before for admission and baselineassessment. They were domiciled in the CRU for 4 days (Day −1, 1, 2 and3) and discharged on Day 4, and were under medical supervision duringthis time. The pre-dose evaluation of all the participants was doneapproximately between 07:00 and 09:00 hours, after an overnight fast ofat least 8 hours. The participants were given free access to drinkingwater until at least one hour before dosing. A venous catheter wasinserted for allowing sampling for PK. At the beginning of each studysession, a single dose of dexmedetomidine sublingual film (Example 1)was administered sublingually by an unblinded staff. The dexmedetomidinesublingual film was retained in the sublingual cavity until dissolved.Evaluations were done every 5 minutes for the first 15 minutes and thenevery 15 minutes to determine the time to dissolution of the film.Subjects were also evaluated for local irritation around the area wherethe film was placed. The subjects were not allowed to sit or stand upduring the first 2 hours after dexmedetomidine sublingual film dosing,except when performing standing BP measurements. After 2 hours, thesubjects were allowed to sit in their beds, however, during sampling,they had to rest in supine or semi-recumbent position. The ECG, BP andoxygen saturation were monitored as per the schedule (Table 29).Subjects were allowed water as desired at least 1 hour after drugadministration. Standard meals were offered at approximately 4, 8, and12 hours after dexmedetomidine sublingual film dosing. However, no foodor drinks were permitted until an investigator confirms that eachsubject was capable of oral intake, based on the degree of sedation andability to control urination. Lavatory visits were also allowed, butalong with an attendant. Day 2 and 3 had no dietary restriction, butthere was complete restriction on smoking and alcohol intake during thelength of CRU stay. After plasma sampling for 24 hours following dosingof dexmedetomidine sublingual film, the safety and tolerabilityassessments were continued until the morning of Day 4 (day ofdischarge), and were repeated on Day 5, Day 7±1 and Day 14±2.

Number of Subjects:

The study evaluated increasing doses of dexmedetomidine sublingual film(example 1—formulation) in 4 cohorts of healthy adult subjects. In thefirst two cohorts (Cohort 1 and Cohort 2), twelve (12) new subjects wereenrolled per cohort, randomized in a ratio of 2:1, i.e. 8 receivingdexmedetomidine sublingual film and 4 receiving Placebo film.

Subjects receiving active drug in Cohort 1/Cohort 2 were to be escalatedto receive high dose of active drug in Cohort 3/Cohort 4 and subjectsreceiving Placebo in Cohort 1/Cohort 2 were to receive Placebo in Cohort3/Cohort 4 respectively. Six new subjects were to be randomized toreceive the active drug in Cohort 3/Cohort 4. Dose-proportionality anddose-exposure response were to be evaluated in the subjects that crossedover to Cohort 3/Cohort 4. The effect of dexmedetomidine sublingual filmon BP, heart rate, RASS score, other AEs and PK parameters were to beevaluated in new subjects who were not previously exposed todexmedetomidine sublingual films. In case of placebo dropouts, whileescalating from Cohort 1 to Cohort 3 or Cohort 2 to Cohort 4, additionalnew subjects were to be randomized to make up the total subjects to 4subjects in Placebo arm of Cohort 3 and Cohort 4.

TABLE 29 Schedule of Assessments Day −1 Day 1 Day 2 & 3 Day 4(Admission; (Study drug (Observation (At time of Day 5 Day 7 ± 1 Day 14± 2 Activity Screen Visit 1) dosing)¹ in CRU) discharge) (Visit 2)⁴(Visit 3)⁴ (Visit 4, EOS)⁴ Informed Consent X Form Demographics XMedical History X X Weight/Body X X X X X X Mass Index Height XInclusion/ X X X Exclusion criteria Randomization X Safety Labs X X X(Chemistry, hematology, U/A, UDS² were done by the unit's local lab)Pregnancy test X (Blood HCG) Pregnancy test X (Urine HCG) Coagulation(PT/INR) X Physical Exam X X X X X X X Complete Neurological X X ExamBrief Neurological X X (at resolution of Exam drowsiness after drugadministration) Vital signs (systolic and X X 0 (predose), 10, 20 and XX X X X diastolic blood pressure, 30 min, then every 15 pulse rate,respiration and min till 6 hours. oxygen saturation) Thereafter prior toPK samples (if any) (±15 min) or hourly until time of sleep and againwith last sample at 24- hour (±15 mins). Standing X (at X (−2 hourspredose, 2, X X blood pressure night) 4, 6 hours postdose) ECG X X Every3 hours (from 0 X X X X X until 6 hours postdose (±15 min). Admit toUnit X Study Drug Preparation X (unblinded pharmacist) Venous Catheter XPlacement Study drug X Sublingually Film buccal X (Section Error!dissolution Reference source not found.) Buccal/Sublingual Exam X X X(at every hour starting X X X X X for local irritation from predoseuntil time of sleep and again with last sample at 24-hour (±15 min).RASS³ X 0 min, every 5 min until drowsiness is achieved (RASS of −1);then every 15 min until resolution of drowsiness Prior to PK samplecollection, till resolution of drowsiness VAS/S 0 min, every 30 minuntil resolution of drowsiness Prior to PK sample collection (±5 min)Training X PK Sampling As per sampling schedule (Section Error!Reference source not found.) Discharge X Concomitant Meds X X X X X X XX Adverse Events X X X X X X X X (Section Error! Reference source notfound.) ECG: electrocardiogram; hCG: human chorionic gonadotropin; PK:pharmacokinetic; PT/INR: prothrombin time/international normalizedratio; RASS: Richmond Agitation Sedation Scale; U/A: Urine Analysis;UDS: Urinary Drug Screen; VAS/S: visual analogue scales/sedation¹Predose assessments had a window of 60 min prior to drugadministration. ²UDS was not done at the discharge day ³If a subject didnot achieve drowsiness (RASS of −1) on or before the 90 minute postdosetimepoint, the procedure was to be performed at 5 minute incrementsuntil 90 minutes postdose, then at 15-minute increments until 120minutes postdose. RASS had a 3 minute window period. ⁴Any abnormal vitalsign measurement, clinical laboratory test, physical examinationfinding, or ECG parameter deemed clinically significant by theinvestigator was to be repeated, including test results obtained on thefinal single-blind study day or upon early termination. For any testabnormality deemed clinically significant, repeat analysis was to beperformed during the follow-up period and until the value returned tobaseline (or within normal limits) or the investigator deemed theabnormality to be of no clinical significance.

Inclusion Criteria:

-   -   1. Healthy males and non-pregnant/non-breast-feeding females        between 18 and 65 years of age, both inclusive.    -   2. Subjects who were capable of giving written informed consent        for the study    -   3. Subjects that had body weight ≥50 kg with body mass index        (BMI) in the range of 19-30 kg/m2, both inclusive    -   4. Subjects having physical examination and vital signs judged        to be within normal limits by the PI or designee.    -   5. Subjects whose clinical laboratory tests (complete blood        count, blood chemistry, and urinalysis) were within normal        limits or are clinically acceptable to the PI or designee.    -   6. Subjects who were sufficiently physically healthy to receive        a SL dose strength of dexmedetomidine sublingual film, and        tolerate drowsiness, in the opinion of the PI or designee.    -   7. Subjects who were fluent in English and have ability to        understand written and verbal protocol-related requirements in        English.    -   8. Subjects who were willing and able to be confined to the CRU        for approximately 4-5 days per dosing cohort and comply with the        study schedule and study requirements.    -   9. Subjects that had reliable intravascular access from which to        draw blood samples.    -   10. Male subjects, if non-vasectomized, must agree to use a        condom with spermicide or abstain from sexual intercourse,        during the trial and for 3 months after stopping the medication.    -   11. Male subject must not donate sperm starting at screening and        throughout the study period, and for 90 days after the final        study drug administration.    -   12. For female subjects of child-bearing potential, the subject        must be willing to practice a clinically accepted method of        birth control from at least 30 days prior to the first        administration of the study medication, during the study, and        for at least 30 days after the last dose of the study        medication.    -   13. For female of non-childbearing potential, the subject was        surgically sterile (i.e. has undergone hysterectomy, bilateral        oophorectomy, or tubal ligation) or in a menopausal state (at        least 1 year without menses), as confirmed by Follicle        stimulating hormone (FSH) levels.

Exclusion criteria:

-   -   1. The subjects with a history of allergic reaction or        intolerance to the study drug or related compounds and        additives.    -   2. The subjects with a history of major surgery within 4 weeks        of screening.    -   3. The subjects with a history of significant traumatic brain        injury.    -   4. The subjects with a history of alcohol or drug dependence by        Diagnostic and Statistical Manual of Mental Disorders IV        criteria during the 6-month period prior to study entry.    -   5. The subjects with a history of or presence of clinically        significant psychiatric illnesses mental retardation, borderline        personality disorder, anxiety disorder, or organic brain        syndrome.    -   6. The subjects with a history of orthostatic hypotension (i.e.,        a sustained reduction of systolic BP (SBP) of at least 20 mmHg        or diastolic BP (DBP) of 10 mmHg, or both, within 3 min of        standing or head-up tilt to at least 60° on a tilt table) and        high vagal tone.    -   7. The subjects who regularly consume large amounts of        xanthine-containing substances (i.e., more than 5 cups of coffee        or equivalent amounts of xanthine-containing substances per        day).    -   8. The subjects who were on maintenance medications that could        inhibit or induce the CYP2A6 enzyme.    -   9. The subjects who had received dexmedetomidine or other        alpha-2-agonists within 1 week of the study date.    -   10. The subjects who had clinically significant sleep apnea or        chronic obstructive pulmonary disease or history of asthma.    -   11. The subjects with suicidal tendency in the judgement of the        PI or designee.    -   12. The subjects with clinical laboratory abnormalities        (including positivity for Hep B, Hep C, HIV) unless treated to        remission status.    -   13. The subjects with abnormal vital signs measurement in the        judgement of the PI or designee, unless treated to remission        status.    -   14. The subjects those were enrolled in another clinical study        (e.g., laboratory or clinical evaluation) or have received an        investigational drug in the past 30 days (or within 5 half-lives        of the investigational drug, if >30 days).    -   15. The subjects that had a resting heart rate of <65 beats per        minute or SBP <110 mmHg or >140 mmHg or DBP <70 mmHg or >100        mmHg at screening and pre-dosing. Have evidence of a clinically        significant 12 lead ECG abnormality. Subjects that previously        failed eligibility criteria at the Screening visit or Day 1        predose due to Exclusion 15 for a resting heart rate <70 beats        per minute but not <65 beats per minute may be rescreened.    -   16. The subjects with an aberrant oral/buccal anatomy,        inflammation or pathology which in the opinion of the PI, may        affect SL drug administration and absorption.    -   17. The subjects with hepatic impairment or who have hepatic        dysfunction defined as a history of hepatic dysfunction and an        Alanine Aminotransferase (ALT) and Aspartate Aminotransferase        (AST) values greater than 2 times normal in the past 6 months        prior to study drug administration.    -   18. The subjects who had donated blood within 30 days prior to        screening or plasma donation within 7 days prior to screening.    -   19. The subject who was part of the study staff personnel or        family members of the study staff personnel.

Study Duration: 39-42 Days.

Treatments Administered

The following treatments were administered on Day 1:Active: Dexmedetomidine hydrochloride SL film at dose levels of 10 μg(1×10 μg film), 20 μg (2×10 μg films) and 40 μg (1×40 μg film)Placebo: Placebo SL filmCohort 1 and Cohort 2 were given 10 μg and 20 μg (2×10 μg films),respectively, Cohort 3 and Cohort 4 received 40 μg of dexmedetomidinesublingual film. All Cohorts were given accompanying Placebo. Except forthe first dose cohort (10 μg dose), each subsequent dose level wasauthorized after safety review of the previous dosing cohort.Dexmedetomidine hydrochloride sublingual film (having dot) was differentfrom Placebo in appearance.

Results:

Data Sets Analyzed

Safety Population

The safety population includes all randomized subjects who received atleast 1 dose of single-blind study drug (n=42).

Pharmacokinetic Population

The PK population includes 28 subjects receiving dexmedetomidinesublingual film. Fourteen subjects who received placebo were notincluded in the PK analysis. For the subjects receiving placebo onlyvisual analogue scale/sedation (VAS/S), Richmond Agitation-SedationScale (RASS), and vital signs (diastolic blood pressure, systolic bloodpressure, pulse rate, respiratory rate, and oxygen saturation) versustime plots were provided.

Pharmacodynamic Population

The PD population includes all randomized subjects who received at least1 dose of single-blind study drug and had post-baseline PD assessmentsperformed (n=42).

Demographic and Other Baseline Characteristics

Overall, the majority of healthy subjects participating in the study(59.5%) were white (non-Hispanic or Latino), a smaller proportion(31.8%) were black (African American). There was 1 (2.4%) Hispanic orLatino subject and 1 (2.4%) Asian subject in the study.

Overall, the number of male and female subjects in the study wascomparable: 22 (52.4%) of all subjects were male and 20 (47.6%) werefemale. The mean age was 44.8 years; the subjects ranged in age from 20to 65 years; 22 (52.4%) subjects were between 20 and 49 years and 20(47.6%) subjects were between >49 and 65 years.

The majority of the subjects in the Placebo group were male (64.3%).Among the subjects administered dexmedetomidine sublingual film, theproportion of male (46.4%) and female (53.6%) subjects was comparable.

The physical measurements in the placebo and dexmedetomidine sublingualfilm group were comparable as well: a mean body mass index (BMI) was25.50 kg/m² in the subjects administered dexmedetomidine sublingual filmand 25.83 kg/m² in the Placebo group.

Pharmacokinetic results: Dexmedetomidine was rapidly absorbed withmeasurable concentrations observed at 10 minutes for all dose levels anduntil 8 hours postdose for the 10 μg dose levels and until 10 and 12hours postdose for 20 μg and 40 μg dose levels, respectively, with ashort mean t_(1/2) that ranged between 1.82-2.16 h. Mean±SD DEX plasmaconcentrations-time profiles at each dose (semi-log scale) plottedagainst sampling time until 8 hrs postdose are presented in FIG. 8 .Dose proportionality assessment indicated that C_(max) and AUCsincreased in a dose-proportional manner with mean C_(max) ranged between29.21 and 122.84 ng/L and mean AUC_(0-inf) ranged between 130.62 and561.57 hr·ng/L. Similar trends were seen with AUC_(last) and AUC₀₋₂₄(Tables 30 to 32; FIGS. 9A to 9C)).

TABLE 30 summarizes pharmacokinetics parameters of 10 microgramsdexmedetomidine sublingual film in healthy volunteers 10 μgdexmedetomidine sublingual film Cmax Tmax t½ AUClast AUC0-INF Subject ID(ng/L) (hr) (hr) (hr*ng/L) (hr*ng/L) 1001 37.94 1.5 2.06 179.19 201.321002 18.27 1.00 1.17 49.45 58.27 1005 33.28 2.00 1.86 116.63 140.07 100735.74 2.00 2.95 142.22 168.59 1009 24.15 3.02 2.70 102.76 1011 30.871.00 2.75 114.35 138.82 1012 24.53 1.50 2.58 98.28 1016 35.19 2.00 1.24119.28 129.17 N 8 8 8 8 6 Mean 30 1.752 2.163 115.271 139.37 SD 6.9300.66 0.693 37.05 47.69 CV % 23.1 37.62 32.0 32.1 34.22 Min 18.27 1.001.17 49.45 58.27 Median 32.08 1.75 2.32 115.49 139.45 Max 37.94 3.022.95 179.19 201.32 Geometric 29.214 1.65 2.051 109.22 130.62 MeanGeometric 25.79 39.08 37.61 38.59 44.75 CV %

TABLE 31 summarizes pharmacokinetics parameters of 20 microgramsdexmedetomidine sublingual film in healthy volunteers 20 μgdexmedetomidine sublingual film Subject Cmax Tmax t½ AUClast AUC0-INF ID(ng/L) (hr) (hr) (hr*ng/L) (hr*ng/L) 2001 0.00 0.00 0.00 2003 83.08 1.002.2 359.59 389.48 2004 65.17 2.00 1.72 259.50 279.49 2007 84.90 1.501.60 401.79 416.92 2011 70.76 2.00 1.85 309.75 337.01 2013 85.92 1.001.85 307.97 330.48 2016 42.34 3.00 1.97 198.79 225.81 2106 66.75 1.501.57 283.34 301.60 N 8 7 7 8 8 Mean 62.37 1.71 1.824 265.092 285.10 SD28.982 0.70 0.221 123.337 129.91 CV % 46.47 40.75 12.1 46.5 45.57 Min0.00 1.00 1.57 0.00 0.00 Median 68.76 1.50 1.85 295.66 316.04 Max 85.923.00 2.20 401.79 416.92 Geometric — 1.601 1.813 — — Mean Geometric —41.30 11.95 — — CV %

TABLE 32 summarizes pharmacokinetics parameters of 40 μg dexmedetomidinesublingual film in healthy volunteers 40 μg dexmedetomidine sublingualfilm Subject Cmax Tmax AUClast AUC0-INF ID (ng/L) (hr) t½ (hr*ng/L)(hr*ng/L) 3011 140.25 1.00 1.78 685.15 709.61 3012 78.69 2.00 2.00427.97 461.18 3013 97.01 1.07 1.76 292.84 310.29 3023 126.60 1.00 1.86493.89 508.98 3026 135.02 1.50 1.38 482.44 499.41 3032 78.06 2.00 378.673114 167.99 1.00 2.05 777.66 806.08 3131 123.52 2.02 2.42 600.88 627.604001 109.62 1.00 1.82 419.51 446.40 4022 204.03 1.00 1.82 664.47 704.504026 123.68 2.00 1.83 507.83 534.00 4130 143.95 2.00 1.97 772.97 798.78N 12 12 11 12 11 Mean 127.37 1.47 1.88 542.02 582.24 SD 35.79 0.49 0.25157.144 158.70 CV % 28.10 33.75 13.44 28.99 27.25 Min 78.06 1.00 1.38292.84 310.29 Median 125.14 1.28 1.83 500.86 534.00 Max 204.03 2.02 2.42777.66 806.08 Geometric 122.84 1.39 1.87 520.58 561.57 Mean Geometric28.87 35.22 13.7 30.84 29.65 CV %

Pharmacodynamic Results:

The sedative effect of dexmedetomidine sublingual film was assessed byRASS and Visual analogue scales/sedation (VAS/S) on day ofdexmedetomidine sublingual film dosing. The assessment included:

Time in minutes and seconds from administration of dexmedetomidinesublingual film until RASS of −1;

-   -   Time in minutes and seconds from RASS of −1 till resolution of        drowsiness;    -   Time in minutes and seconds from SL administration of        dexmedetomidine sublingual film till its complete dissolution or        30 minutes.    -   Richmond Agitation Sedation Scale

All RASS scores assessed during the study ranged between −2 (LightSedation) and 0 (Alert and Calm). The baseline score for all subjectswas 0 (Alert and Calm). Overall, a total of 14 subjects achieveddrowsiness (RASS of −1) across all treatments. Of these, 2 received 10μg dose group, 4 received 20 μg dose group, 5 received 40 μg dose group,and 3 received Placebo. Two subjects also achieved light sedation (RASSof −2), 1 received 10 μg dose group and the other one received Placebo.

The mean times to achieve drowsiness from baseline for subjectsadministered dexmedetomidine sublingual film and placebo is summarizedin Table 33. Overall, the time to achieve drowsiness was variable acrossall treatment groups and ranged from 19 minutes to 85 minutes indexmedetomidine sublingual film groups and from 19 minutes 17 seconds to107 minutes 29 seconds in placebo group. No statistically significantbetween-group differences were observed for either 10 μg or 40 μgtreatment groups.

The duration from onset of drowsiness (RASS of −1) until resolution forsubjects administered dexmedetomidine sublingual film and Placebo issummarized in Table 34. Overall, the duration from onset of drowsiness(RASS of −1) until resolution was variable across all treatment groupsand ranged from 05 minutes 05 seconds to 91 minutes. Mean duration insubjects administered dexmedetomidine sublingual film was 48 minutes 24seconds, and subjects administered placebo presented a mean duration of37 minutes 25 seconds.

TABLE 33 Achievement of Drowsiness (in minutes:seconds) from BaselineAssessed by RASS of −1 Dexmedetomidine sublingual film Cohort 1 Cohort 2Cohort 3 Cohort 4 Cohort 3 + 4 (10 μg) (20 μg) (40 μg) (40 μg) (40 μg)Active Placebo Active Active Placebo Active Active Placebo Statistics (N= 8) (N = 4) (N = 8) (N = 8) (N = 4) (N = 4) (N = 12) (N = 6) n 2 2 4 31 2 5 1 Mean (SD) 31:30 65:47 59:16 47:30 19:17 24:00 38:60 19:17 (3:32)(58:58) (18:16) (10:27) (7:40) (15:15) Median 31:30 65:47 54:20 44:2019:17 24:00 39:00 19:17 Min, Max 29:00, 24:50, 44:00, 39:00, 19:17,19:00, 19:00, 19:17, 34:00 107:29 85:00 59:10 19:17 29:00 59:10 1947P-value vs 1.000 0.5000 0.6667 Placeboa aP-value is based on anon-parametric two-sided (exact) Wilcoxon test. n—number of subjects whohave reached at least RASS of −1 at any time in the first 2 hours

TABLE 34 Duration from RASS of −1 till Resolution of Drowsiness (inminutes:seconds) Dexmedetomidine sublingual film Cohort Cohort 1 Cohort2 Cohort 3 Cohort 4 3 and 4 Overall Pooled 10 μg 20 μg 40 μg 40 μg 40 μgActive^(a) Placebo^(a) Overall^(a) Statistics (N = 8) (N = 8) (N = 8) (N= 4) (N = 12) (N = 28) (N = 14) (N = 42) n 2 4 3 2 5 11 2 13 Mean (SD)84:30 53:49 28:00 32:03 29:37 48:24 37:25 46:43 (9:12) (10:56) (30:29)(38:07) (28:52) (28:45) (10:38) (26:44) Median 84:30 52:39 15:01 32:0315:01 59:00 37:25 45:12 Min, Max 78:00, 44:00, 6:10, 5:05, 5:05, 5:05,29:54, 5:05, 91:00 66:00 62:50 59:00 62:50 91:00 44:56 91:00 ^(a)OverallActive, Pooled Placebo and Overall columns include assessment counts notsubject level counts. n—number of subjects who have reached at leastRASS of −1 at any time in the first 2 hours

Visual Analogue Scales/Sedation:

The subjective sedative effect of dexmedetomidine was assessed by meansof VAS. Subjects were asked to score their feeling on a 100-mmhorizontal scale, with 0 indicating very sleepy and 100 indicating veryalert. Overall, VAS scores were variable with the lowest scores beinggenerally observed at the 1.0 and 1.5-hour timepoints for subjects dosedwith dexmedetomidine sublingual film. Mean scores observed at pre-dose0.5, 1, 1.5- and 2-hours following treatment with dexmedetomidinesublingual film or placebo and P-values are presented in Table 35 andFIGS. 10A-10B. There were no statistically significant between-groupdifferences (Active vs. Placebo) observed in Cohorts 1 (10 μg), Cohort 2(20 μg) and Cohorts 3 and 4 combined (40 μg dose). Statisticallysignificant differences were only seen in Cohort 3 (40 μg). However, thestatistical significance in this cohort was also reported for thepre-dose assessment (P<0.05; Table 35) indicating that the studyenvironments and score variability may have affected the outcome.

Dexmedetomidine Sublingual Film Dissolution Time:

A single dose of dexmedetomidine sublingual film was administeredsublingually. For 20 μg dose cohort, two (2) 10 μg films wereadministered simultaneously. The drug film was retained in thesublingual cavity until it had dissolved. There was an evaluation every5 minutes for the first 15 minutes, and then every 15 minutes todetermine the time to dissolution of the film. Mean, median, and min andmax dissolution time for each treatment group in minutes:seconds arepresented in Table 36. Overall, duration from the SL administration ofdexmedetomidine sublingual film or Placebo film until its completedissolution was variable and ranged from 3 minutes to 44 minutes 11second. Mean (SD) and median dissolution times were similar fordexmedetomidine sublingual film (14:09 (11:33); 11:11, minutes: seconds)and Placebo (13:32 (12:49); 8:28, minutes: seconds) films. No subjectpresented aberrant oral/buccal anatomy or inflammation during the buccalmucosal irritation examination.

Safety Evaluation:

Based on the results in this study, the following safety conclusions canbe made:

-   -   There were no deaths or serious TEAEs reported in the study. One        subject administered dexmedetomidine sublingual film 10-μg had a        decrease in heart rate >30 beats per minute (withdrawal        criterion) therefore had become ineligible to participate in        Cohort 3. An overall summary of AEs is provided in Table 37.    -   A total of 52 TEAEs were reported by 25 of the 28 subjects (89%)        administered dexmedetomidine sublingual film and 20 TEAEs were        reported by 10 of the 14 subjects (71%) administered placebo.        All TEAEs were recovered by the end of the study.    -   Subjects administered dexmedetomidine sublingual film reported        TEAEs with an incidence of 75% for 10 μg dose group, 88% for 20        μg dose group and 100% for 40 μg dose group. Drug-related TEAEs        were reported with an incidence of 75% following administration        of 10 μg dose group, 88% following administration of 20 μg dose        group, 92% following administration of 40 μg dose group and 64%        following administration of placebo.

The most experienced TEAE during the study was somnolence, which wasreported with a slightly higher frequency at doses of 20 μg and 40 μg(75% each) compared to the 10 μg dose and placebo (50% each) (Table 38).

The majority of TEAEs were mild in severity in all treatment groups withonly few moderate TEAEs reported. Moderate TEAEs were experiencedfollowing administration of 10 μg dose ( 1/12; 8%), 40 μg dose ( 2/30;7%) and administration of placebo(4/20; 20%). No severe TEAEs werereported in this study.

No subject dosed in this study required hemodynamic/medicalinterventions for maintaining BP, cardiac interventions for maintainingheart rate or respiratory interventions for maintaining oxygensaturation. No subject was withdrawn due to a TEAE. The data is furtherdepicted in FIGS. 11 to 15 .

Two subjects presented symptomatic changes in vital signs that wereconsidered clinically significant and reported as vital signs relatedTEAEs. One subject administered placebo had a decrease in DBP and SBPthat were recorded as drug-related TEAEs of moderate and mild intensity,respectively and 1 subject administered 40 μg dose group had decreasesin heart rate that were recorded as 2 drug-related TEAEs of mildintensity. All TEAEs were resolved within 1 day from onset.

There were no clinically significant changes in laboratory parametersand ECG assessments. No physical examination finding was consideredclinically significant by the investigator. All neurologicalexaminations performed during the study were normal and no subjectpresented aberrant oral/buccal anatomy or inflammation during the buccalmucosal irritation examination.

TABLE 35 Summary of Visual Analogue Scales/Sedation Cohort 1 Cohort 2Cohort 3 (10 μg) (20 μg) (40 μg) Active Placebo Active Placebo ActivePlacebo Timepoint Statistics (N = 8) (N = 4) (N = 8) (N = 4) (N = 8) (N= 4) Pre-dose n 8 4 8 4 8 4 Mean (SD) 95.5 97.8 97.4 86.5 74.8 100(12.73) (4.50) (6.25) (21.30) (35.29) (0.00) P-value 1    0.2384    0.0485* 0.5 Hour n 8 4 8 4 8 4 Mean (SD) 78.8 90.0 74.4 55.8 73.093.0 (23.50) (11.52) (20.87) (35.61) (25.72.) (12.68) P-value    0.4788   0.2788     0.0465* 1.0 Hour n 5 4 8 4 8 4 Mean (SD) 67.6 93.8 43.048.5 42.8 94.3 (33.30) (6.65) (38.26) (48.50) (32.98) (10.18) P-value   0.3175    0.9737     0.0121* 1.5 Hour n 8 4 8 4 7 3 Mean (SD) 63.080.3 43.8 53.5 53.0 99.7 (29.69) (30.18) (40.02) (48.64) (41.68) (0.58)P-value    0.4586    0.4869     0.0167* 2.0 Hour n 8 4 8 4 7 3 Mean (SD)81.8 74.5 54.9 59.0 50.9 99.7 (25.97) (42.19) (38.92) (47.79) (36.22)(0.58) P-value    0.9253    0.8848     0.0167* Cohort 4 Cohort 3 + 4 (40μg) (40 μg) Active Placebo Active Placebo Overall Timepoint Statistics(N = 4) (N = 2) (N = 12) (N = 6) (N = 42) Pre-dose n 4 2 12 6 60 Mean(SD) 86.8 70.5 78.8 90.2 87.5 (25.84) (41.72) (31.78) (24.09) (24.18)P-value   0.8    0.139 0.5 Hour n 4 2 12 6 60 Mean (SD) 75.0 64.5 73.783.5 76.3 (22.67) (48.79) (23.71) (28.09) (24.24) P-value   0.8    0.2203 1.0 Hour n 4 2 12 6 57 Mean (SD) 71.5 64.0 52.3 84.2 61.7(22.61) (49.50) (32.13) (28.22) (34.97) P-value   0.8     0.0691 1.5Hour n 4 2 11 5 56 Mean (SD) 78.8 70.0 62.4 87.8 65.0 (25.59) (42.43)(37.52) (26.72) (36.06) P-value    0.9333     0.0627 2.0 Hour n 3 2 10 554 Mean (SD) 73.0 72.5 57.5 88.8 67.9 (24.88) (37.48) (33.56) (23.93)(34.28) P-value   0.8     0.0513 P-values are calculated for Active vsPlacebo for each cohort. P-value based on non-parametric two-sided(exact) Wilcoxon test. *Statistically significant between-groupdifference (Active vs Placebo)

TABLE 36 Duration from SL Administration (in minutes:seconds) ofDexmedetomidine sublingual film till its Complete Dissolution (PDPopulation) Dexmedetomidine sublingual film Cohort 3 and Cohort 1 Cohort2 Cohort 3 Cohort 4 Cohort 4 Overall Pooled 10 μg 20 μg 40 μg 40 μg 40μg Active* Placebo* Overall* Statistics (N = 8) (N = 8) (N = 8) (N = 4)(N = 12) (N = 28) (N = 14) (N = 42) n 8 8 8 4 12 28 13 41 Mean (SD) 9:0323:49 14:26 4:26 11:06 14:09 13:32 13:58 (7:52) (12:36) (10:04) (2:24)(9:30) (11:33) (12:49) (11:49) Median 5:11 29:01 14:05 3:23 8:09 11:118:28 8:28 Min, Max 3:00, 8:00, 3:18, 3:00, 3:00, 3:00, 3:00, 3:00, 24:3044:01 29:01 8:00 29:01 44:01 44:11 44:11 *Overall Active, Pooled Placeboand Overall columns include assessment counts not subject level counts

TABLE 37 Summary of Adverse Events Dexmedetomidine sublingual filmCohort 3 and Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 4 10 μg 20 μg 40μg 40 μg 40 μg Overall Placebo Overall (N = 8) (N = 8) (N = 8) (N = 4)(N = 12) (N = 28) (N = 14) (N = 42) n (%) n (%) n (%) n (%) n (%) n (%)n (%) n (%) AEs reported 75  TEAEs reported 12  10  24  6 30  52  20 72  Subjects with at least one 6 7 8 4 12 25 10 35 TEAE^(a) (75.0)(87.5) (100.0) (100.0) (100.0) (89.3) (71.4) (83.3) Subjects with atleast one 6 7 8 3 11 24 9 33 drug-related TEAE^(a) (75.0) (87.5) (100.0)(75.0) (91.7) (85.7) (64.3) (78.6) TEAEs relationship^(b) Possiblyrelated 4 2 5 0 5 11 4 15 (33.3) (20.0) (20.8) (16.7) (21.2) (20.0)(20.8) Probably related 2 0 7 1 8 10 3 13 (16.7) (29.2) (16.7) (26.7)(19.2) (15.0) (18.1) Definitely related 3 8 12 3 15 26 10 36 (25.0)(80.0) (50.0) (50.0) (50.0) (50.0) (50.0) (50.0) Related 0 0 0 0 0 0 1 1(5.0) (1.4) Unrelated/unlikely 3 0 0 2 2 5 2 7 (25.0) (33.3) (6.7) (9.6)(10.0) (9.7) TEAEs severity^(b) Mild 11 10 22 6 28 49 16 65 (91.7)(100.0) (91.7) (100.0) (93.3) (94.2) (80.0) (90.3) Moderate 1 0 2 0 2 34 7 (8.3) (8.3) (6.7) (5.8) (20.0) (9.7) Severe 0 0 0 0 0 0 0 0 STEAEsreported^(b) 0 0 0 0 0 0 0 0 Subjects with at least one 0 0 0 0 0 0 0 0STEAE^(a) Subject with at least one 0 0 0 0 0 0 0 0 study drug-relatedSTEAE^(a) Subjects with at least one 0 0 0 0 0 0 0 0 TEAE leading tostudy discontinuation^(a) Deaths^(a) 0 0 0 0 0 0 0 0 AE: adverse event;N: number of subjects; n (%): number and percent of subjects included;SAE: serious adverse event; STEAE: serious treatment-emergent adverseevent; TEAE: treatment-emergent adverse event Notes: Overall Active,Pooled Placebo and Overall columns include assessment counts not subjectlevel counts. Possibly Related, Probably Related, Related, or DefinitelyRelated categories are counted under Drug-Related. ^(a)Percentages arebased on the number of subjects in the Safety population in eachtreatment group. ^(b)Percentages are based on the total number oftreatment-emergent adverse events reported in each treatment group

TABLE 38 Treatment-Emergent Adverse Events Reported in Two or MoreSubjects Overall Dexmedetomidine sublingual film Cohort 3 and Cohort 1Cohort 2 Cohort 3 Cohort 4 Cohort 4 10 μg 20 μg 40 μg 40 μg 40 μgOverall Placebo Overall System Organ Class (N = 8) (N = 8) (N = 8) (N =4) (N = 12) (N = 28) (N = 14) (N = 42) Preferred Term n (%) n (%) n (%)n (%) n (%) n (%) n (%) n (%) Subjects with at 6 7 8 4 12  25  10  35 least one TEAE (75.0) (87.5) (100.0)  (100.0)  (100.0)  (89.3) (71.4)(83.3) Nervous system 5 7 7 2 9 21 8 29  disorders (62.5) (87.5) (87.5)(50.0) (75.0) (75.0) (57.1) (69.0) Somnolence 4 6 7 2 9 19 7 26  (50.0)(75.0) (87.5) (50.0) (75.0) (67.9) (50.0) (61.9) Dizziness 1 1 6 0 6 8 210  (12.5) (12.5) (75.0) (50.0) (28.6) (14.3) (23.8) Headache 1 1 0 0 02 3 5 (12.5) (12.5)  (7.1) (21.4) (11.9) Gastrointestinal 2 1 3 1 4 7 29 disorders (25.0) (12.5) (37.5) (25.0) (33.3) (25.0) (14.3) (21.4)Nausea 1 0 2 0 2 3 0 3 (12.5) (25.0) (16.7) (10.7)  (7.1) Dry Mouth 0 01 1 2 2 1 3 (12.5) (25.0) (16.7)  (7.1)  (7.1)  (7.1) Vomiting 1 0 1 0 12 1 3 (12.5) (12.5) (8.3)  (7.1)  (7.1)  (7.1) General disorders and 1 02 1 3 4 1 5 administration site (12.5) (25.0) (25.0) (25.0) (14.3) (7.1) (11.9) conditions Fatigue 1 0 2 0 2 3 0 3 (12.5) (25.0) (16.7)(10.7)  (7.1)

Conclusion: Overall, PK, PD and safety results presented in this studysupport further development of dexmedetomidine sublingual film for theacute treatment of agitation associated with dementia, schizophrenia,and bipolar disorders as a minimally invasive rapid-delivery dosage formof dexmedetomidine.

EXAMPLE 8: CLINICAL STUDY OF THE EFFICACY (SEDATION AND ANTI-AGITATION),PHARMACOKINETICS AND SAFETY OF DEXMEDETOMIDINE INFUSED INTRAVENOUSLY INSUBJECTS SUFFERING FROM SCHIZOPHRENIA

A Key objective of the study was to determine the optimal intravenous(IV) dose of dexmedetomidine hydrochloride in the target population interms of efficacy and safety to achieve arousable sedation (RASS of −1)which can be reversed by verbal stimulation. When this goal was achievedin each participant, the IV infusion of dexmedetomidine hydrochlorideceased. Another Key Objective of the study was to determine thereduction in the level of agitation, as determined by their PEC score,at the doses to achieve a RASS of −1.

In addition, the following Secondary Objectives were:

-   -   1. Determine how rapidly the drug can be administered up to the        total dose needed to achieve RASS −1.    -   2. Determine how long the calming effect persists after        discontinuation of study drug administration.    -   3. Determine whether any adverse effects on blood pressure,        heart rate, or respiratory drive occurs before or coincident        with the achievement of Primary Objective. Stopping rules for        blood pressure and heart rate, indicating a clinically        significant event, are:        -   drop in systolic BP<90 mm of Hg.        -   drop in diastolic BP<60 mm of Hg        -   drop below 50 beats per minute

Participants were provided written informed consent before any studyrelated procedures were performed. All participants were screened forinclusion and exclusion criteria. The participants were admitted to thesite at screening (Day −1), the day before the infusion. Baselineassessments were performed on Day −1, as well as on the day of infusion(Day 1). The participants were on Day 1 prepared for the infusion,infused for up to 3 hours and monitored for resolution of sedation andany decreases in blood pressure or heart rate which met stoppingcriteria. The participants were not discharged from the research unituntil three hours after resolution of any reduction in the level ofarousal (e.g., RASS −1) and/or resolution of any decrease in bloodpressure or heart rate meeting stopping criteria. The PrincipalInvestigator had discretion to keep the participant overnight at thesite the evening of Day 1 for extended monitoring and then dischargehome the participant on Day 2 if the Principal Investigator or designeedetermined that the participant has returned to their baseline state.

The study population included 14 participants, 10 active and 4 placebo.Patients 5, 7, 8 and 9 received placebo. Patients 1, 2, 3, 4, 11, 12,14, 16, 17, 18 were infused with intravenous dexmedetomidinehydrochloride, starting at a rate of 0.2 mcg/kg/hr, and rising by 0.1mcg/kg/hr every 30 minutes until stopping criteria were reached up or toa maximum duration of 3 hours (Table 39). Participants randomized toplacebo received a matching intravenous infusion of placebo solution.

TABLE 39 Study Treatments Treatment Formulation FrequencyDexmedetomidine PRECEDEX ® Continuous infusion, hydrochloride incrementevery 30 minutes Placebo Normal Saline Continuous infusion

Once the participant was drowsy (RASS −1), the infusion was stopped. Themaximum total dose administered was 1.6 mcg/kg/hr, when either thedesired level of sedation was achieved or the maximum allowable decreasein either systolic or diastolic blood pressure or heart rate occurred.

The participants were continuously monitored during the study by thesite personnel, including monitoring blood pressure and heart rate.Intermittent electrocardiograms were taken from the start of theinfusion through resolution of the sedation and/or any adverse effectson blood pressure or heart rate.

Whenever the above stopping criteria was met, the site stopped theinfusion and the site continued to monitor the participant's vital signsevery 15 minutes until the participant has reached their baselineparameters or in the judgment of the principal investigator theparticipant has reached a stable and acceptable level of blood pressureand heart rate. Return to baseline parameters is defined as BP fallingwithin 15 mm of Hg of baseline reading prior to drug administration orHR falling within 10 beats per minute of baseline reading prior to drugadministration.

In the event the investigator deemed the fall in blood pressure or heartrate to be clinically significant, suitable remedial drugs could beadministered in addition to termination of the dexmedetomidinehydrochloride infusion, based on investigator's judgement.

Adverse events (AEs), including serious adverse events (SAEs), wereassessed, recorded, and reported in accordance with FDA guidance. Shouldany SAE occur, the study would be stopped until a cause for the SAE wasdetermined.

Efficacy Assessment:

(1) Richmond Agitation Sedation Scale (RASS): The desired endpoint washow rapidly drowsiness (RASS −1) could be achieved without causingchanges in heart rate or blood pressure greater than that specified bythe protocol. The study also monitored how long the participant remainedat that level of sedation; sedation was considered resolved when theparticipant was awake and spontaneously responding.

(2) PANS S: Change from baseline for mildly agitated patients

(3) Clinical Global Impression of Improvement (CGI-I) (NationalInstitute of Mental Health 1976) ranging from 1 (very much improved) to7 (very much worse) compared with baseline. Each participant was rated,based on the severity of agitation, at 15 and 30 minutes for every doseinfusion, at the endpoint, and at the time the participant returned tobaseline (in terms of level of arousal). CGI-I focused on the severityof agitation rather than the severity of the illness.

(4) After the infusion was stopped, the participants were judged for thesuitability for discharge by the principal investigator or designee aswitnessed by a return to their baseline level of alertness and awarenesswith no impairment in balance, gait, and reaction time as determined bythe principal investigator or designee.

RESULTS

(A) Efficacy Study

RASS (Richmond Agitation-Sedation Scale)

9 out of 10 patients in the treatment arm (subjects 1-3, 11, 12, 14, and16-18) achieved a RASS score of at least −1, while no patients in theplacebo arm (subjects 5, and 7-9) experienced meaningful sedation (seeFIG. 16 and Table 40).

TABLE 40 Depicts the RASS score of Schizophrenia patients receivinginfusion of dexmedetomidine hydrochloride and normal saline RASS valuesafter infusion start Patient No. 1 2 3 4 5 7 8 9 11 12 14 16 17 18Infusion (minutes) T T T T P P P P T T T T T T 0 1 3 1 1 1 1 1 1 1 1 1 11 0 15 −2 −1 30 0 0 0 1 1 1 1 0 0 0 0 0 45 0 −1 60 0 −1 0 1 1 0 1 0 0 00 75 −1 −1 −1 −1 90 0 1 0 0 1 0 105 120 0 0 0 0 1 −1 135 0 150 0 0 0 1165 180 0 0 0 1 T—treatment arm; P—placebo arm

PEC (PANS S Excitement Component)

9 out of 10 patients in the treatment arm (subjects 1-4, 11, 12, 14, 16and 17) had agitation reduced to a minimum (as measured by a PEC scoreof 7 or below) (see Table 41 and FIG. 17 ).

TABLE 41 Depicts the PEC data of schizophrenia patients receivinginfusion of dexmedetomidine and normal saline PEC values after infusionstart Patient No. Time 1 2 3 4 5 7 8 9 11 12 14 16 17 18 (Mins) T T T TP P P P T T T T T T 0 9 16 12 9 11 12 9 13 13 13 10 10 10 15 5 13 12 910 12 9 13 13 13 9 9 8 30 12 10 8 9 9 8 12 11 13 6 6 7 45 11 7 8 9 8 812 9 10 6 6 5 60 9 6 7 8 8 8 13 9 10 5 7 75 7 7 8 8 7 11 7 8 5 5 90 7 79 7 11 6 105 7 8 8 7 10 5 120 7 8 8 7 10 135 8 7 7 9 150 8 7 7 9 165 8 87 9 180 8 8 7 10 T—treatment arm; P—placebo arm

(B) Pharmacokinetic Study: (PK Study)

The level of dexmedetomidine in the plasma of patients was also measuredover the time of infusion. The results are tabulated in Table 42. Themaximum dexmedetomidine concentrations in schizophrenic patients(C_(max)) ranged from about 22.45 μg/mL to about 406.3 μg/mL. Time toreach C_(max) ranged from about 15 minutes to about 105 minutes. Meaninfusion rate is 0.36 mcg/kg/hr with the maximum rate ranging from about0.2 mcg/kg/hr to about 0.6 mcg/kg/hr (see FIGS. 18 to 20 ).

TABLE 42 depicts the plasma concentrations (pg/mL) of schizophreniapatients at different timepoints during the infusion of dexmedetomidinehydrochloride and normal saline Plasma level concentration (picogram/ml)Time 1 2 3 4 5 7 8 9 11 12 14 16 17 18 (Mins) T T T T P P P P T T T T TT 0 BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ 15 22.45 BLQ BLQBLQ BLQ BLQ 41.01 BLQ BLQ 2.56 15.87 48.36 30 14.72 BLQ BLQ BLQ BLQ BLQBLQ BLQ 62.91 44.87 52.66 15.59 BLQ 54.53 45 BLQ BLQ BLQ BLQ BLQ BLQ124.07 50.51 46.53 41.17 39.93 60 BLQ BLQ BLQ BLQ BLQ 150.47 108.6 406.367.88 75 BLQ BLQ BLQ BLQ BLQ 158.54 72.26 90 44.3 BLQ BLQ BLQ BLQ 237.83105 BLQ BLQ BLQ BLQ 267.3 120 BLQ BLQ BLQ BLQ 135 BLQ BLQ BLQ BLQ 150BLQ BLQ BLQ BLQ 165 BLQ BLQ BLQ BLQ 180 BLQ BLQ BLQ BLQ Total 19 75 60149 180 180 180 179 68 103 64 66 36 30 duration of infusion (Mins)*BLQ—below limit of quantification T—Treatment; P—Placebo

Discussion: The administration of dexmedetomidine hydrochloride by theIV route produced a >=50% reduction in PEC score in a total of 7 of 10subjects, with one subject (Patient 1) responding at a C_(max) of 22μg/mL. 5 of 10 subjects (Patients 1, 2, 3, 16 and 17) exhibited a 40%reduction in PEC score at a Cmax of =<72 μg/mL. The good response ratesat these plasma exposure levels indicated that sublingualdexmedetomidine hydrochloride administration at similar or higher Cmaxexposure levels achieved good anti-agitation effects. As demonstrated inExample 7 above, sublingual dexmedetomidine hydrochloride administeredto healthy volunteers produced good plasma exposure levels at doses of10, 20 and 40 micrograms, indicating that such doses were suitable forobtaining good anti-agitation effects (e.g. as measured by a reductionin PEC score) in agitated subjects, including subjects withschizophrenia, without also producing clinically meaningful detrimentaleffects on blood pressure and/or heart rate.

EXAMPLE 9: A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-BLIND,PLACEBO-CONTROLLED STUDY TO DETERMINE EFFICACY AND SAFETY OFDEXMEDETOMIDINE SUBLINGUAL FILM IN AGITATION ASSOCIATED WITHSCHIZOPHRENIA

Objectives:

Primary Objective

To determine if a single dose of Dexmedetomidine sublingual filmeffectively reduced symptoms of acute agitation associated withschizophrenia, schizoaffective disorder or schizophreniform disorderassessed using the Positive and Negative Syndrome Scale—ExcitedComponent (PEC) change from baseline as compared to placebo.

Key Secondary Objective:

To determine the earliest time where an effect on agitation was apparentas measured by the change from baseline in PEC total score in contrastwith placebo.

Other exploratory objectives:

-   -   1. Overall clinical improvement after drug administration as        measured by the Clinical Global Impression—Improvement Scale        (CGI-I) score.    -   2. Agitation-Calmness Evaluation Scale (ACES) scores at 2, 4 and        8 hrs after dose administration.    -   3. Change from baseline in total PEC score over time measured        from 10 min through 24 hrs after dosing.    -   4. PEC Responders and CGI-I Responders at 2 hours following dose        of Dexmedetomidine sublingual film, compared with placebo:        -   a. PEC responders were defined as those who achieve at least            a 40% reduction in PEC total score from baseline at or            before 2 hours post-dose.        -   b. CGI-I responders were defined as subjects with a score of            1 or 2 on the CGI-I scale (the CGI-I non-responders were            defined as subjects with scores from 3 to 7 at 2 hours).    -   5. Time to rescue medication during the entire 24 hrs        Post-treatment Evaluation Period for subjects who received        Dexmedetomidine sublingual film compared to placebo.    -   6. Proportion of subjects per treatment group who received        rescue medication by 4 hrs and within 24 hrs after dosing.    -   7. Duration of calming effect as described by the change from        baseline in PEC total score, and ACES score at 2, 4 and 8 hrs        after dosing.    -   8. Describe effect on overall psychotic symptoms and subscales        (PANSS total, positive, negative, and general psychopathology        subscales)    -   9. Determine the safety profile of Dexmedetomidine sublingual        film as measured by vital signs and treatment-emergent adverse        event reports and vital signs.    -   10. Describe the overall tolerability in terms of adverse event        reports and local site (oral/sublingual) tolerability of oral        film.    -   11. Descriptive pharmacokinetics of Dexmedetomidine sublingual        film in the patient population.    -   12. Determine patient acceptability, taste and likability of        study medication using likert scales to capture subject's        acceptability, opinion on taste and questions regarding        likability.

Study Design: This was a randomized, double-blind, placebo-controlledPhase III study assessing efficacy, safety and tolerability ofdexmedetomidine sublingual film dosing in adult (18-75 years old) malesand females with acute agitation associated with schizophrenia,schizoaffective disorder, or schizophreniform disorder. This in-clinicstudy randomized subjects 1:1:1 to receive Dexmedetomidine sublingualfilm (180 m or 120 μg dose of DEX) or matching placebo film. Therandomization was be stratified by age; age <65 and age ≥65.

Eligible subjects (acutely agitated subjects with schizophrenia,schizoaffective, or schizophreniform disorder) might be identified inoutpatient clinics, mental health, psychiatric or medical emergencyservices including medical/psychiatric observation units, or as newlyadmitted to a hospital setting for acute agitation or alreadyhospitalized for chronic underlying conditions. Subjects were domiciledin a clinical research setting or hospitalized to remain under medicalsupervision while undergoing screening procedures to assess eligibility.

Upon confirmation of eligibility, subjects were randomized to receiveeither 180 μg or 120 μg Dexmedetomidine sublingual film or matchingplacebo. At the time of dosing, patients were instructed on how to takethe investigational product sublingually, and that they should retainthe investigational product in the sublingual cavity until dissolved.The patient was self-administered under the supervision of a trainedstaff member. If the patient was unable to self-administer, the eventwas recorded, and the subject's participation was concluded. In theevent of persistent or recurrent agitation, investigators might chose torepeat dose at 90 μg or 60 μg (half of 180 μg or 120 μm film) after the2-hour time point as measured by a PEC change from baseline <40% but inthe absence of safety concerns. Patients could only be re-dosed if theywere hemodynamically stable, not hypotensive (must be greater than 90/60diastolic/systolic) and not bradycardic (must be greater than 60 bpm).Patients also could not be re-dosed if they were orthostatic (a drop of20 points in either SBP or DBP) or if they were experiencing an AE thatwhen assessed by the PI precludes redosing. The maximum number of repeatdoses per subject was 2, during the 12 hours post first dose. Dosesmight not be administered sooner than 2 hours after a previous dose. Ifthe PEC change from baseline was >40% repeat dosing was not allowed.

Participants were also be evaluated for local irritation around the areawhere the film was placed. Efficacy and safety assessments wereconducted periodically before and after dosing. All efforts should bemade to have the patient perform all assessments as per protocol. VitalSigns, pulse oximetry, and ECG with rhythm strip were measured as perschedule of assessments (Table 43), prior to any PK assessments.Participants were allowed water as desired 15 minutes after completionof dosing. Safety and tolerability assessments were conducted at varioustimepoints.

Any abnormal vital sign measurement, clinical laboratory test, physicalexamination finding, or ECG parameter deemed clinically significant bythe investigator repeated, including test results obtained on the finalstudy day or upon early termination. For any test abnormality deemedclinically significant, repeat analysis was performed during thefollow-up period and until the value returns to baseline (or withinnormal limits) or the investigator deems the abnormality to be stableand no longer of clinical concern.

Approximately 4 mL of venous blood (to obtain a minimum of 1.2 mLplasma) was taken into K2-EDTA tubes at set time intervals for thedetermination of plasma concentrations of study drug (or Placebo). ThePK plasma samples were collected within 10 min of the scheduled samplingtime on Day 1.

Number of subjects (planned): Approximately 375 subjects were enrolledat up to 30 study sites in the United States.

Diagnosis and Main Criteria for Eligibility:

Inclusion Criteria:

-   -   (1) Male and female patients between the ages of 18 to 75 years,        inclusive.    -   (2) Patients who had met DSM-5 criteria for schizophrenia,        schizoaffective, or schizophreniform disorder.    -   (3) Patients who were judged to be clinically agitated at        Baseline with a total score of ≥14 on the 5 items (poor impulse        control, tension, hostility, uncooperativeness, and excitement)        comprising the PANSS Excited Component (PEC).    -   (4) Patients who had a score of ≥4 on at least 1 of the 5 items        on the PEC or PEC score at baseline    -   (5) Patients who read, understood and provided written informed        consent.    -   (6) Patients who were in good general health prior to study        participation as determined by a detailed medical history,        physical examination, 12-lead ECG with rhythm strip, blood        chemistry profile, hematology, urinalysis and in the opinion of        the Principal Investigator.    -   (7) Female participants, if of child-bearing potential and        sexually active, and male participants, if sexually active with        a partner of child-bearing potential, who agreed to use a        medically acceptable and effective birth control method        throughout the study and for one week following the end of the        study. Medically acceptable methods of contraception that might        be used by the participant and/or his/her partner included        abstinence, birth control pills or patches, diaphragm with        spermicide, intrauterine device (IUD), condom with foam or        spermicide, vaginal spermicidal suppository, surgical        sterilization and progestin implant or injection. Prohibited        methods included: the rhythm method, withdrawal, condoms alone,        or diaphragm alone.

Exclusion Criteria:

-   -   (1) Patients with agitation caused by acute intoxication,        including positive identification of alcohol by breathalyzer or        drugs of abuse (with the exception of THC) during urine        screening.    -   (2) Patients treated within 4 hours prior to study drug        administration with benzodiazepines, other hypnotics or oral or        short-acting intramuscular antipsychotics.    -   (3) Treatment with alpha-1 noradrenergic blockers (terazosin,        doxazosin, tamsulosin, alfuzosin, or prazocin) or other        prohibited medications.    -   (4) Patients with significant risk of suicide or homicide per        the investigator's assessment, or any patient with an answer of        “yes” to item 4 or 5 on the CSSRS.    -   (5) Female patients who had a positive pregnancy test at        screening or are breastfeeding.    -   (6) Patients who had hydrocephalus, seizure disorder, or history        of significant head trauma, stroke, transient ischemic attack,        subarachnoid bleeding, brain tumor, encephalopathy, meningitis,        Parkinson's disease or focal neurological findings.    -   (7) History of syncope or other syncopal attacks, current        evidence of hypovolemia, orthostatic hypotension(average of 1, 3        and 5 min measurements), a screening and baseline heart rate of        <55 beats per minutes or systolic blood pressure <110 mmHg or        diastolic BP<70 mmHg.    -   (8) Patients with laboratory or ECG abnormalities considered        clinically significant by the investigator or qualified designee        [Advanced heart block (second-degree or above atrioventricular        block without pacemaker), diagnosis of Sick sinus syndrome] that        would had clinical implications for the patient's participation        in the study.    -   (9) Patients with serious or unstable medical illnesses. These        include current hepatic (moderate severe hepatic impairment),        renal, gastroenterologic, respiratory, cardiovascular (including        ischemic heart disease, congestive heart failure),        endocrinologic, or hematologic disease.    -   (10) Patients who had received an investigational drug within 30        days prior to the current agitation episode.    -   (11) Patients who were considered by the investigator, for any        reason, to be an unsuitable candidate for receiving        dexmedetomidine; e.g. patients with a history of allergic        reactions to dexmedetomidine.

Study Treatments

Test Product, Dose, and Mode of Administration:

Dexmedetomidine hydrochloride was a thin film formulation of DEX forsublingual (SL) administration. Dosing delivers 180 μg or 120 μg of DEXsublingually. The product is a small, solid-dose film formulation,approximately 193.6 mm² in area and 0.7 mm thick, designed to completelydissolve in the SL space within 1-3 minutes.

Reference Therapy, Dosage and Mode of Administration:

Matching placebo films was taken sublingually as described above.

Duration of Treatment: 1 day

Study Procedures

Subjects provided written informed consent before any study-relatedprocedures were initiated, including the cessation of prohibitedconcomitant therapy.

The schedule of events performed during the study were provided in Table43

TABLE 43 Schedule of Events Treatment Evaluation Day 1 ScreeningPre-Dose¹ Post Dose Time¹ Time point Pre- −1 hr to 10 20 30 45 1 1.5 2 46 8 Activity treatment time 0 min min min min hr hr hr hr hr hr InformedConsent X Medical History X Demographics X Weight X Height X BMI XAlcohol X breathalyzer MINI X Physical Exam X Safety Labs² X ECG withrhythm X X X strip ³ Pulse oximetry X X X X X X Resting vital X X X X XX X X signs⁴ Orthostatic vital signs⁴ X X X X X Admit to Unit XInclusion/Exclusion X X criteria Randomization X Study drug Xadministration¹⁰ PANSS⁹ X X PCRS⁵ X X X PEC⁵ X X X X X X X X X X X XACES⁵ X X X X CGI-Severity⁶ X X CGI-Improvement⁶ X X X X C-SSRS X Buccal(SL) X X X assessment for local irritation⁷ Likert scales X LikabilityQuestion X PK Sampling⁸ X X X Concomitant X X X Medications AdverseEvents X X X Treatment Evaluation Day 2, 3, and 7 Day 2 Follow- Day 3Day 7 Screening Up (+1) Discharge (+2) Time point 24 hr ActivityPre-treatment (−9/+12 hr) End of Study Informed Consent X MedicalHistory X Demographics X Weight X X Height X BMI X Alcohol Xbreathalyzer MINI X Physical Exam X X Safety Labs² X X X ECG with rhythmX X strip ³ Pulse oximetry Resting vital signs⁴ X X X X Orthostaticvital X X X X signs⁴ Admit to Unit X Inclusion/Exclusion X criteriaRandomization Study drug administration¹⁰ PANSS⁹ X PCRS⁵ X X PEC⁵ X XACES⁵ CGI-Severity⁶ X CGI-Improvement⁶ C-SSRS X X Buccal (SL) Xassessment for local irritation⁷ Likert scales Likability Question PKSampling⁸ Concomitant X X X X Medications Adverse Events X X X X Notesto the Schedule of Events: ¹Pre-dose assessments had a window of 60minutes prior to dose with the exception of PEC and ACES which wereperformed within 15 minutes of dosing (15 to 0 min). All post-doseassessments had a window of −5/+15 minutes through the 1.5 hourassessments, −5/+25 minutes for the 2 hour assessments (with theexception of the PEC which will have a +/−5 minute window) and ±30minutes for the 4, 6 and 8 hour assessments. ²Safety Labs werechemistry, hematology, urinalysis, UDS (local lab, only conducted atscreening), alcohol breathalyzer (only conducted at screening), andurine pregnancy (only conducted at screening). Screening/enrollmentlabs: local labs drawn within 7 days prior to screening might sufficewith the exception of urine drug screen. If results not available on thesame day, a ‘desktop’ or non-CLIA test might be performed; to confirm,results from a CLIA-certified laboratory was recorded once available.Central Labs was performed on Screening, Day 3 and Day 7. ³ ECG forpre-dose did not need to be repeated if screening ECG was conducted onthe day of dosing. ECGs collected following treatment were to beperformed prior to PK assessments. ⁴Resting (recumbent) vital signs(SBP, DBP and HR) were taken upon having the subject recumbent for 5 minat Screening, Pre-dose and at 30 min, 1, 2, 4, 6, 8 and 24 hours postdose, as well as Day 3 and Day 7. Triplicate measurements performed incase of Systolic BP <90 mmHg, Diastolic BP <60 mmHg or Pulse <60 bpm.Orthostatic measurements (SBP, DBP, HR, respiratory rate andtemperature) was taken upon having the subject stand, with measurementstaken after 1, 3 and 5 minutes at Screening, Pre-dose, 2, 4, 8 and 24hours post first dose, as well as Day 3 and Day 7. ⁵PEC was performed atScreening, Pre-dose (within 15 min prior to dose) and at 10, 20, 30, 45min; 1, 1.5, 2, 4, 6, 8 and 24 hours post dose. The PCRS must beperformed prior to PEC rating, when required. At 6 and 24 hrs the PECrating must be performed before the PANSS interview. ACES was performedat Pre-dose (within 15 min of dose), 2, 4 and 8 hrs post dose.⁶CGI-Severity was performed at Screening and pre-dose. CGI-Improvementwas performed at 30 minutes, 1, 2 and 4 hours post dose. ⁷Buccal exam at30 min, 2, 4 and 24 hr post-dose for local irritation. ⁸PK blood sampleswere collected 1, 4, and 8 hr (while awake) after dose. A sample mightnot be collected if the Physician indicated in source documents that thepatient was in a mental state that was not conducive to PK samplecollection. Non-compliance or refusal of all or any PK draw was notexclusionary nor result in ET. Vital signs were to be done prior to PKsample draws, when performed at the same timepoints. ⁹Pre-dose PANSSmight be administered at any time prior to dosing on the day of dosingand 6 and 24 hrs (−1/+2 hr) post-dose. At 6 and 24 hrs PANSS interviewmust be performed after PEC rating. The 6 hour and 24 hr PANSS wasconducted with reference to the predose PANSS. ¹⁰The investigator mightchoose to re-dose the patient with half of a film after the 2 hourpost-dose assessments are performed if the PEC change from baseline is<40%. Patients could be re-dosed up to 2 times during 12 hours postfirst dose. All assessments listed in this Schedule of Events at the 2hour post first dose timepoint repeated at 2 hours post every re-dose.

Criteria for Evaluation:

Efficacy assessment: Assessment of Drug Effects on acute agitation wasdone by the Positive and Negative Syndrome Scale—Excited Component(PEC). The PEC comprises 5 items associated with agitation: poor impulsecontrol, tension, hostility, uncooperativeness, and excitement; eachscored 1 (minimum) to 7 (maximum). The PEC, the sum of these 5subscales, thus ranges from 5 to 35.

Overall agitation and sedation were evaluated with theAgitation-Calmness Evaluation Scale (ACES), where 1 indicates markedagitation; 2—moderate agitation; 3—mild agitation; 4—normal behavior;5—mild calmness; 6—moderate calmness; 7—marked calmness; 8—deep sleep;and 9—unarousable.

The overall clinical improvement in agitation in response to treatmentwas also be measured by the Clinical Global Impressions—Improvement(CGI-I). CGI-I scores range from 1 to 7:0=not assessed (missing), 1=verymuch improved, 2=much improved, 3=minimally improved, 4=no change,5=minimally worse, 6=much worse, 7=very much worse.

Safety and tolerability assessments: AEs, clinical laboratory tests, ECGwith rhythm strip, pulse oximetry, and vital signs were monitored fortolerability assessment. All observed and volunteered AEs were recorded.The relationship of AEs to the study drug were graded as not related,unlikely/remotely related, possibly related, probably related ordefinitely related by the investigators. Vital signs including systolicblood pressure (SBP), diastolic blood pressure (DBP), and heart ratewere monitored. The application site of the SL preparation (buccalmucosa) was inspected for any signs of local irritation

Additional Assessments:

Demographics, Medical and Psychiatric History, psychotic symptoms(PANSS), Smoking history, Prior and Concomitant Medication, PhysicalExamination, Pregnancy

Pharmacokinetics: A sparse PK sampling of plasma concentrations atspecified timepoints were reported. A population PK/PD analysis ofplasma concentration vs. clinical response was reported using a separateSAP and report. A graphical assessment of PK vs. vital signs and otherpotential PD parameters were included.

Statistical Analysis:

Efficacy Analyses

The primary efficacy endpoint of the study was the absolute change frombaseline in the PEC total score at 120 min. The intent to treatpopulation was analyzed and consist of all patients who took any studymedication and who had both baseline and at least 1 efficacy assessmentafter dosing. The key secondary endpoints were: change from baseline inthe PEC score at 90 min, 60 min, 45 min, 30 min, 20 min and 10 min.Other exploratory endpoints were same as listed under exploratoryobjectives.

Safety Analyses: Safety data analysis was conducted on all subjectsreceiving at least 1 dose of study drug. The number and percentage ofsubjects experiencing 1 or more AEs were summarized by treatment,relationship to study drug, and severity. AEs were coded using theMedical Dictionary for Regulatory Activities (Med DRA) terminology.Listings of subjects who experienced withdrawal due to an AE, seriousAEs and/or death will be presented. Laboratory parameters weresummarized by treatment using descriptive statistics and data listingsof clinically significant abnormalities. Vital signs and ECG data weresummarized by changes from baseline values using descriptive statistics.

Pharmacokinetic Analyses

Plasma concentrations and concentration-time data for dexmedetomidinewere used to calculate PK parameters; these data and results werereported separately. All pharmacokinetic parameters were calculatedusing non-compartmental analysis using WinNonlin Version 5.2 or higher.Actual sampling times were used in all pharmacokinetic analyses. Perprotocol times were used to calculate mean plasma concentrations forgraphical displays. Other PK analyses were performed as appropriate.

Results Summary:

Demographics

The demographics and baseline characteristics is shown below in Table44.

TABLE 44 Demographics Dexmedetomidine Sublingual film 180 μg 120 μgPlacebo Overall (N = 126) (N = 129) (N = 126) (N = 381) Mean age (years)46.0 (11.91) 45.7 (11.32) 45.1 (11.13) 45.6 (11.43) Female N (%) 44(34.9) 52 (40.3) 44 (34.9) 140 (36.7) Race (% white/% non-white)16.7/83.3 25.6/74.4 16.7/83.3 19.7/80.3 BMI 32.53 (7.8) 31.24 (7.6)32.56 (7.4) 32.10 (7.6) Diagnosis Schizophrenia 85.70% 87.60% 80.20%84.50% Schizophrenia 14.30% 12.40% 19.80% 15.50% Baseline PEC means 17.617.5 17.6 NA

3. Efficacy

Dexmedetomidine sublingual film significantly improved the severity ofagitation from baseline as measured by PEC, ACES scales and CGI-Iscores. Key efficacy findings at 2 hours post-dose are presented below.

(a) Primary Efficacy Endpoint (PEC reduction): a reduction in the PECscore (PANSS or the Positive and Negative Syndrome Scale, ExcitatoryComponent) for agitation was observed with rapid calming withoutexcessive sedation at the clinical regulatory endpoint and at earliertime-points. The primary efficacy endpoint was the mean change frombaseline in PEC total score at 2 hours (120 minutes) compared toplacebo. There were 2 dose cohorts (120 μg(N=129) and 180 μg (N=126))and 126 placebo patients. Active patients in each of the 2 dose cohortswere compared to placebo patients. The change from baseline in PEC at 2hours for patients treated with dexmedetomidine sublingual film wascompared with placebo using a mixed model repeated measures (MMRM)analysis, with baseline PEC, treatment group, time, the interactionbetween treatment groups and time, and the interaction between baselinePEC and time as covariates.

The efficacy of dexmedetomidine hydrochloride sublingual film asmeasured by PEC reduction is dose-responsive and robust. The decreasefrom baseline in PEC score in the 180 dose group showed significantresponse with a −10.3 mean change from baseline (CFB) total PEC score at2 hours post dosing compared to placebo (Table 45 and FIGS. 21A and21B). Mean changes from baseline were −8.5 points for the 120 μgtreatment groups, compared to placebo (−4.8 Mean change). Additionally,as early onset of action is an important attribute for therapy inreducing agitation, the 180 μg group showed a statistically significantseparation from placebo as early as 20 minutes post dosing (FIG. 21A andFIG. 21B). Further, the decrease from baseline in PEC score in the 180μg and 120 μg dose groups showed significant responses at 6 hours postdosing compared to placebo (FIG. 21B).

PEC Responder Analyses: The proportion of treatment responders, definedas those with a 40% decrease from baseline in PEC total score at 2 hourspost dose, was greatest in the 180 group (87% for 180 μg, 67% for 120μg) as compared to placebo (34%) (TABLE 45). The durability of calmingeffects of the 180 μg dose was remarkably prolonged with a sustainedstatistically significant reduction in PEC evident after 24 hrs.

TABLE 45 Summary of Change from Baseline at 2 hours in PANSS- PEC TotalScore and Percent of Responders at 2 hours in the PEC Score by TreatmentGroup Endpoint Dexmedetomidine (120 min) Sublingual film PEC Total 120μg 180 μg score N Placebo (N = 126) (N = 126) Change from N = 126 −4.8−8.5 *** −10.3 *** Baseline (180 μg) (LSM) N = 126 (120 μg) Response °126 34% 67% 87% ° Proportion achieving ≥ 40% PEC reduction, * p < 0.025;*** p < 0.0001

Secondary Efficacy Endpoints:

Changes in secondary efficacy measures (i.e., ACES and CGI-I scores) at2 hours post-dose were consistent with the results for PEC total scoresand were indicative of improvement in symptoms of agitation aftertreatment with dexmedetomidine sublingual film.

ACES scores: A secondary objective for this study was to evaluate theduration of calming effect of dexmedetomidine sublingual thin film drugutilizing the Agitation-Calmness Evaluation Scale (ACES) collected atpre-dose, 2 hr, and 4 hr after first dose. The ACES assessment wasconsistent with the analysis of the primary endpoint, and metstatistically significance for calming as measured by ACES at two hourscompared to placebo in 120 μg and 180 μg (120 μg; p=0.0001) and (180 μg;p<0.0001). At 2 hours after dosing, subjects in the 120 μg and 180 μgtreatment groups showed significantly greater improvements relative toplacebo in ACES scores (+ about 2.8 [P<0.0001] for 120 μg; + about 3.75[P<0.0001] for 180 μg, compared to placebo of + about 1.0). Theimprovements at 4 hours post-dose were similar (+ about 2.8 [P<0.0001]for 120 μg; + about 3.2 [P<0.0001] for 180 μg, compared to placebo of +about 1.0). (FIG. 22 ).

CGI-scores: The percentage of subjects achieving CGI-I scores of 1 or 2(‘very much improved’ or ‘much improved’) at 2 hours post-dose wassignificantly higher in the 120 μg group (about 65% [p<0.0001]) and inthe 180 μg dose group (about 90% [p<0.0001]), compared with placebo(about 35%). Significant improvements were also observed at 30 minutes,1 hour, and 4 hours after dosing for both treatment groups [in the 180μg dose group (p<0.0001) and in the 120 dose group (p<0.0075)] (FIG. 23).

Conclusion: Dexmedetomidine sublingual film treatment significantlyimproved the severity of agitation from baseline as measured by PEC,CGI-I, and ACES scales in schizophrenia patients. The primary efficacyendpoint was met in 120 μg, and 180 μg treatment groups as there wassignificant improvements in PEC total scores from baseline at 2 hourspost-dose with mean changes of −8.5 and −10.3 points, respectively,versus −4.8 for placebo. Reduction in agitation was observed as early as20 minutes compared to placebo. Further, changes in secondary efficacymeasures (ie, CGI-I and ACES scores) at 2 hours post-dose wereconsistent with the results for PEC total scores and were indicative ofimprovement in symptoms of agitation after treatment withDexmedetomidine sublingual film.

EXAMPLE 10: A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-BLIND,PLACEBO-CONTROLLED STUDY TO DETERMINE THE EFFICACY AND SAFETY OFDEXMEDETOMIDINE HYDROCHLORIDE SUBLINGUAL FILM IN SUBJECTS WITH AGITATIONASSOCIATED WITH BIPOLAR DISORDER (SERENITY II)

Objectives:

Primary Endpoint

The primary efficacy endpoint of the study was the absolute change frombaseline in the PEC total score at 2 hours. The intent to treatpopulation was analyzed and consists of all patients who took any studymedication and who had both baseline and at least 1 efficacy assessmentafter dosing. Observations recorded after use of rescue medication werecensored.

Key Secondary Endpoint Included:

The key secondary efficacy endpoint was the earliest time where aneffect on agitation was apparent as measured by change from baseline PECtotal score in contrast with placebo.

Exploratory Endpoints Included:

-   -   1. Overall clinical improvement after drug administration as        measured by the Clinical Global Impression—Improvement Scale        (CGI-I) score.    -   2. Agitation-Calmness Evaluation Scale (ACES) scores at 2, 4 and        8 hrs. after dose administration.    -   3. Change from baseline in total PEC score over time measured        from 10 min through 24 hrs. after dosing.    -   4. PEC Responders and CGI-I Responders at 2 hours following dose        of dexmedetomidine hydrochloride, compared with placebo:        -   a. PEC responders were defined as those who achieved at            least a 40% reduction in PEC total score from baseline at or            before 2 hours post-dose.        -   b. CGI-I responders were defined as subjects with a score of            1 or 2 on the CGI-I scale (the CGI-I non-responders were            defined as subjects with scores from 3 to 7 at 2 hours).    -   5. Time to rescue medication during the entire 24 hrs.        Post-treatment Evaluation Period for subjects receiving        dexmedetomidine hydrochloride compared to placebo.    -   6. Proportion of subjects per treatment group who received        rescue medication by 4 hrs. and within 24 hrs. after dosing.    -   7. Duration of calming effect as described by the change from        baseline in PEC total score, and ACES score at 2, 4 and 8 hrs.        after dosing.    -   8. Determined the safety profile of dexmedetomidine        hydrochloride as measured by vital signs and treatment-emergent        adverse event reports.    -   9. Described the overall tolerability in terms of adverse event        reports and local site (oral/sublingual) tolerability of oral        film.    -   10. Descriptive pharmacokinetics of dexmedetomidine        hydrochloride in the patient population.    -   11. Determined patient acceptability, taste and likability of        study medication using Likert scales to capture subject's        acceptability, opinion on taste and questions regarding        likability.    -   12. Characterized the patient population utilizing the Young        Mania Rating Scale (YMRS).

Study Design:

The study enrolled approximately 381 subjects randomized 1:1:1 to doseregimens of 180 μg, 120 μg dexmedetomidine hydrochloride, or placebostratified by age <65 and age ≥65. The doses were selected based on theresults of the prior Phase Ib clinical trial.

Male and female adults with acute agitation associated with bipolar I orII disorder were enrolled.

Eligible subjects (acutely agitated subjects with bipolar I or IIdisorder, generally hypomanic, manic or mixed episodes) may beidentified in outpatient clinics, mental health, psychiatric or medicalemergency services, including medical/psychiatric observation units, oras newly admitted to a hospital setting for acute agitation or alreadyin hospital for chronic underlying conditions. Subjects were domiciledin a clinical research setting or hospitalized to remain under medicalsupervision while undergoing screening procedures to assessedeligibility.

Upon confirmation of eligibility, subjects were randomized to 180 μgdexmedetomidine hydrochloride sublingual film or 120 μg dexmedetomidinehydrochloride sublingual film or matching placebo. Efficacy and safetyassessments were conducted periodically before and after dosing.

Vital signs, pulse oximetry and ECG with rhythm strip were measured asper schedule of assessments, prior to any PK assessments. Participantswere allowed water as desired 15 minutes after completion of dosing.Safety and tolerability assessments were conducted at varioustimepoints. Please refer to the Table 46 for Schedule of events.

Any abnormal vital sign measurement, clinical laboratory test, physicalexamination finding, or ECG parameter deemed clinically significant bythe investigator were repeated, including test results obtained on thefinal study day or upon early termination. For any test abnormalitydeemed clinically significant, repeat analysis performed during thefollow-up period and until the value returns to baseline (or withinnormal limits) or the investigator deemed the abnormality to be stableand no longer of clinical concern.

Approximately 4 mL of venous blood (to obtain a minimum of 1.2 mLplasma) was taken into K2-EDTA tubes at set time intervals for thedetermination of plasma concentrations of study drug (or placebo). ThePK plasma samples were collected within 10 min of the scheduled samplingtime on Day 1. Blood samples were collected per Table 46 Schedule ofEvents.

Discussion of Study Design

This was a definitive study to support the safety and efficacyevaluation of dexmedetomidine hydrochloride sublingual film for theacute treatment of agitation in bipolar disorder. The study was designedto characterize the efficacy, safety and tolerability of dexmedetomidinehydrochloride sublingual film in agitation associated with bipolardisorder. A dose of dexmedetomidine hydrochloride was chosen based onresults that showed rapid efficacy in a large proportion of subjects waswell tolerated and had an acceptable safety profile. In the event ofpersistent or recurrent agitation, investigators might chose toadminister an additional reduced dose of 90 μg or 60 μg (half of 180 μgor 120 μg film) after the 2-hour time point as measured by a PEC changefrom baseline ≤40%, but in the absence of safety concerns. Patientscould only be re-dosed if they were hemodynamically stable, nothypotensive (must be greater than 90/60 systolic/diastolic) and notbradycardic (must be greater than 60 bpm). Patients also could not bere-dosed if they were orthostatic (a drop of >20 mm Hg systolic, or 10mm Hg diastolic) or if they were experiencing an Adverse Event (AE) thatin the assessment of the PI precludes re-dosing. The maximum number ofrepeat doses per subject is 2, during the 12 hours post-first dose.Doses might not be administered sooner than 2 hours after a previousdose. If the PEC change from baseline is ≥40%, repeat dosing was notallowed.

Placebo was chosen as a comparator to more accurately assess efficacy aswell as safety and tolerability. The randomized, double-blindparallel-group design ensures the sponsor, all subjects, and study staffinvolved were shielded from treatment assignment and outcomes andtherefore minimized any potential bias. The randomization ratio providedan additional element that ensured blinding by decreasing the odds ofguessing treatment arms.

Diagnosis and Main Criteria for Eligibility:

Inclusion Criteria

-   -   1. Male and female patients between the ages of 18 to 75 years,        inclusive.    -   2. Patients who had met DSM-5 criteria for bipolar I or II        disorder, generally hypomanic, manic or mixed episodes.    -   3. Patients who were judged to be clinically agitated at        Screening and Baseline with a total score of >14 on the 5 items        (poor impulse control, tension, hostility, uncooperativeness,        and excitement) comprising the PANSS Excited Component (PEC).    -   4. Patients who had a score of >4 on at least 1 of the 5 items        on the PEC at Baseline.    -   5. Patients who read, understand and provided written informed        consent.    -   6. Patients who were in good general health prior to study        participation as determined by a detailed medical history,        physical examination, 12-lead ECG with rhythm strip, blood        chemistry profile, hematology, urinalysis, and in the opinion of        the Principal Investigator.    -   7. Female participants, if of child-bearing potential and        sexually active, and male participants, if sexually active with        a partner of child-bearing potential, who agreed to use a        medically acceptable and effective birth control method        throughout the study and for one week following the end of the        study. Medically acceptable methods of contraception that might        be used by the participant and/or his/her partner include        abstinence, birth control pills or patches, diaphragm with        spermicide, intrauterine device (IUD), condom with foam or        spermicide, vaginal spermicidal suppository, surgical        sterilization, and progestin implant or injection. Prohibited        methods include: the rhythm method, withdrawal, condoms alone,        or diaphragm alone.

Exclusion Criteria

-   -   1. Patients with agitation caused by acute intoxication,        including positive identification of alcohol by breathalyzer or        drugs of abuse (with the exception of THC) during urine        screening.    -   2. Use of benzodiazepines or other hypnotics or antipsychotic        drugs in the 4 hours before study treatment.    -   3. Treatment with alpha-1 noradrenergic blockers (terazosin,        doxazosin, tamsulosin, alfuzosin, or prazosin) or other        prohibited medications.    -   4. Patients judged to be at serious risk of suicide must be        excluded.    -   5. Female patients who had a positive pregnancy test at        screening or are breastfeeding.    -   6. Patients who had hydrocephalus, seizure disorder, or history        of significant head trauma, stroke, transient ischemic attack,        subarachnoid bleeding, brain tumor, encephalopathy, meningitis,        Parkinson's disease or focal neurological findings.    -   7. History of syncope or other syncopal attacks, current        evidence of hypovolemia, orthostatic hypotension (average of 1,        3 and 5 min measurements), a screening and baseline heart rate        of <55 beats per minutes or systolic blood pressure <110 mmHg or        diastolic BP<70 mmHg.    -   8. Patients with laboratory or ECG abnormalities considered        clinically significant by the investigator or qualified designee        [Advanced heart block (second-degree or above atrioventricular        block without pacemaker), diagnosis of Sick sinus syndrome] that        would had clinical implications for the patient's participation        in the study.    -   9. Patients with serious or unstable medical illnesses. These        include current hepatic (moderate-severe hepatic impairment),        renal, gastroenterologic, respiratory, cardiovascular (including        ischemic heart disease, congestive heart failure),        endocrinologic, or hematologic disease.    -   10. Patients who had received an investigational drug within 30        days prior to the current agitation episode.    -   11. Patients who were considered by the investigator, for any        reason, to be an unsuitable candidate for receiving        dexmedetomidine hydrochloride, e.g. patients with a history of        allergic reactions to dexmedetomidine hydrochloride.

Study Treatments

Method of Assigning Subjects to Treatment Groups

Upon confirmation of eligibility, subjects were randomized to 180 μgdexmedetomidine hydrochloride film or 120 μg dexmedetomidinehydrochloride film or placebo. Randomization was 1:1:1 (180 μg or 120 μgdexmedetomidine hydrochloride or placebo and stratified by age <65, age≥65) with 125 patients assigned to each arm by a permuted block design.Study randomization was computer generated.

Test Product, Dose, and Mode of Administration:

Dexmedetomidine hydrochloride was in a film formulation for sublingual(SL) administration. Dosing delivered 180 μg or 120 μg ofdexmedetomidine hydrochloride sublingually. The product was a small,solid-dose film formulation, approximately 193.6 mm² in area and 0.7 mmthick, designed to completely dissolve in the SL space within about 1-3minutes.

Treatment Administration

At the time of dosing, patients were instructed on how to takedexmedetomidine hydrochloride film sublingually, and that they shouldretained the dexmedetomidine hydrochloride film in the sublingual cavityuntil dissolved. The patient self-administered under the supervision ofa trained staff member. If the patient was unable to self-administer,the event was recorded, and the subject's participation was concluded.

In the event of persistent or recurrent agitation, investigators mightchoose to re-dose at 90 μg or 60 μg (dividing the 180 μg or 120 μg filmin half) after the 2-hour time point as measured by a PEC change frombaseline ≤40% but in the absence of safety concerns.

Study Procedures

Subjects provided written informed consent before any study-relatedprocedures were initiated, including the cessation of concomitanttherapy.

The schedule of events performed during the study was provided in Table46.

TABLE 46 Schedule of Events Treatment Evaluation Day 1 ScreeningPre-Dose¹ Post Dose Time¹ Time point Pre- −1 hr to 10 20 30 45 1 1.5 2 46 8 Activity treatment time 0 min min min min hr hr hr hr hr hr InformedConsent X Medical History X Demographics X Weight X Height X BMI XAlcohol Breathalyzer X MINI X Physical Exam X Safety Labs² X ECG withrhythm strip ³ X X X Pulse oximetry X X X X X X Resting vital signs⁴ X XX X X X X X Orthostatic vital signs⁴ X X X X X Admit to Unit XInclusion/Exclusion X X criteria Randomization X Study drug Xadministration⁹ YMRS X PCRS⁵ X X X PEC⁵ X X X X X X X X X X X X ACES⁵ XX X X CGI-Severity⁶ X X CGI-Improvement⁶ X X X X C-SSRS X X Buccal (SL)assessment for X X X local irritation⁷ Likert Settles X LikabilityQuestions X Pharmacokinetic Sampling⁸ X X X Concomitant Meds X X XAdverse Events X X X Treatment Evaluation Day 2, 3 and 7 - Post DoseTime¹ Day 2 Follow- Day 3 Day 7 Screening Up (+1) Discharge (+2) Timepoint Pre- 24 hr End of Activity treatment (−9/+12 hr) Study InformedConsent X Medical History X Demographics X Weight X X Height X BMI XAlcohol X Breathalyzer MINI X Physical Exam X X Safety Labs² X X X ECGwith rhythm strip ³ X X Pulse oximetry Resting vital signs⁴ X X X XOrthostatic X X X X vital signs⁴ Admit to Unit X Inclusion/Exclusion Xcriteria Randomization Study drug administration⁹ YMRS X PCRS⁵ X X PEC⁵X X ACES⁵ CGI-Severity⁶ X CGI-Improvement⁶ C-SSRS X X X Buccal (SL)assessment for X local irritation⁷ Likert Scales Likability QuestionsPharmacokinetic Sampling⁸ Concomitant Meds X X X X Adverse Events X X XX Notes to the Schedule of Events: ¹Pre-dose assessments had a window of60 minutes prior to dose with the exception of PEC and ACES which wereperformed within 15 minutes of dosing (15 to 0 min). All post-doseassessments had a window of −5/+15 minutes through the 1.5 hourassessments, −5/+25 minutes for the 2 hour assessments (with theexception of the PEC which had a +/−5 minute window) and ±30 minutes forthe 4, 6 and 8 hour assessments and YMRS could be performed at any time.²Safety Labs included chemistry, hematology, urinalysis, UDS (local lab,only conducted at screening), alcohol breathalyzer (only conducted atscreening), and urine pregnancy (only conducted at screening)Screening/enrollment labs: local labs drawn within 7 days prior toscreening might suffice with the exception of mine drug screen. Ifresults not available on the same day, a 'desktop' or non-CLIA testmight be performed; to confirm, results from a CLIA-certified laboratoryshould be recorded once available. Central Labs should be performed onScreening, Day 3 and Day 7. ³ ECG for pre-dose does not need to berepeated if screening ECG was conducted on the day of dosing. ECGscollected following treatment were performed prior to PK assessments.⁴Resting (recumbent) vital signs (SBP, DBP and HR) were taken uponhaving the subject recumbent for 5 min at Screening, Pre-dose and at 30min, 1, 2, 4, 6, 8 and 24 hours post dose, as well as Day 3 and Day 7.Triplicate measurements were performed in case of Systolic BP <90 mmHg,Diastolic BP <60 mmHg or Pulse <60 bpm. Orthostatic measurements (SEP,DBP, HR, respiratory rate) were taken upon having the subject stand,with measurements taken after 1, 3 and 5 minutes and temperature weretaken at Screening, Pre-dose, 2, 4, 8 and 24 hours post first dose, aswell as Day 3 and Day 7. ⁵PEC was performed at Screening, Pre-dose(within 15 min prior to dose) and at 10, 20, 30, 45 min; 1, 1.5, 2, 4,6, 8 and 24 hours post dose. The PCRS must be performed prior to PECrating, when required. ACES was performed at Pre-dose (within 15 min ofdose), 2, 4 and 8 hrs post dose. ⁶CGI-Severity was performed atScreening and pre-dose. CGI-Improvement was performed at 30 minutes, 1,2 and 4 hours post dose. ⁷Buccal examined at 30 min, 2, 4 and 24 hrpost-dose for local irritation. ⁸PK blood samples were collected 1, 4,and 8 hr (while awake) after dose. A sample might not be collected ifthe Physician indicated in source documents that the patient was in amental state that was not conducive to PK sample collection.Non-compliance or refusal of all or any PK draw was not exclusionary norresult in ET. Vital signs were to be done prior to PK sample draws, whenperformed at the same timepoints. ⁹The investigator might chose tore-dose the patient after the 2 hour post-dose assessments are performedif the PEC change from baseline is ≤40%. Patients could re-dosed aftercompleting the 2 hour post first dose assessments. Repeat dosingadministers half of a film. Patients could redosed twice in the 12 hourperiod post first dose. All assessments listed in this Schedule ofEvents at the 2 hour post first dose timepoint should be repeated at 2hours post every re-dose. Assessments at 4, 6, or 8 hour post first dosethat occur within 1 hour of a post re-dose assessment were not requiredto be performed

Study Assessments

Efficacy

The effect of study drug was evaluated using several validatedinstruments as described below.

PANSS—Excitatory Component (PEC)

Agitation-Calmness Evaluation Scale (ACES)

CGI-S and CGI-I

Clinical Global Impression of Severity (CGI-S) was rated based upon theseverity of agitation at screening and pre-dose (immediately prior tostart of dosing).

Severity of illness was assessed based on following scale:

-   -   0=Not assessed    -   1=Not at all ill    -   2=Borderline mentally ill    -   3=Mildly ill    -   4=Moderately ill    -   5=Markedly ill    -   6=Severely ill    -   7=Among the most extremely ill subjects

Drug response on agitation was evaluated by the Clinical GlobalImpressions—Improvement (CGI-I). It was performed at 30 minutes, 1, 2and 4 hrs post dose. The CGI-I scores range from 1 to 7:

-   -   0=not assessed (missing),    -   1=very much improved,    -   2=much improved,    -   3=minimally improved,    -   4=no change,    -   5=minimally worse,    -   6=much worse,    -   7=very much worse

Both CGI-I and CGI-S were focused on the severity of agitation ratherthan the severity of the overall illness of bipolar disorder.

Young Mania Rating Scale (YMRS)

The YMRS was an 11-item scale evaluating mania symptoms based on thepatient's subjective report of their clinical condition. It was used tocharacterize the patient population enrolled in the study.

Placebo-Control Reminder Script (PCRS)

The Placebo-Control Reminder Script (PCRS)© Hassman and Cohen, 2019,Version 5.0 educates clinical trial participants of key causes of theplacebo and nocebo effects, namely the tempering of participant studyexpectations, reminding subjects what a placebo is and how that relatesto their reporting of symptoms and potential side effects, andexplaining how interactions with research site staff differ from theirexperience with previous providers. To do this, the PCRS informssubjects that they were to be honest about their symptoms, site staffhad no expectations of symptom improvement or worsening and was notdisappointed if they feel better, worse or the same, and askedparticipants to explain in their own words its content to ensurecomprehension. The PEC Rater was read the PCRS study source beforeadministering the PEC to each subject at each visit (time point) listedon the study specific PCRS, typically taking about 2 minutes to read.

Likert Scales

After dosing with the study drug, subjects assessed their preference ofthe study medication by answering the statements “I like the taste ofthe medication” and “The medication is acceptable” using a five-levelLikert scale as below: Strongly disagree Disagree Neither agree nordisagree Agree Strongly agree

Drug Likability

Subjects responded to open ended questions regarding their experience.Additional comments about aftertaste, smell, dissolve time, etc. wereasked as Yes/No questions with Yes responses prompting an explanationfield.

Safety

Safety was assessed during the study by the monitoring and recording ofAEs, clinical laboratory test results (hematology, biochemistry, andurinalysis), vital sign measurements (systolic and diastolic bloodpressures, heart rate measured as pulse, respiratory rate, andtemperature), ECG, and physical examination findings. Should a knownsafety issue be identified (e.g. a high incidence of severe hypotensionor bradycardia in the active 180 μg dose arm or the 120 μg arm), theDSMB notified the sponsor. Should this occur, sponsor notified FDA, andsponsor might chose to continue dosing the patients at a lower dose.

Pharmacokinetics

Blood samples (4 ml) were collected per Table 46-Schedule of Events. Foreach subject, up to 3 blood samples (12 mL of blood) were collectedduring the study for PK analysis. In addition, approximately 30 mL ofblood was collected at screening, approximately 15 mL of blood wascollected at Day 3 Discharge, and approximately 15 mL of blood wascollected at Day 7(+2) for clinical laboratory testing. The total volumeof blood collected during the study was expected to be approximately 72mL. For each subject, up to 3 blood samples (12 mL of blood) werecollected during the study for PK analysis. In addition, approximately30 mL of blood was collected at screening, approximately 15 mL of bloodwas collected at Day 3 Discharge, and approximately 15 mL of blood wascollected at Day 7(+2) for clinical laboratory testing. The total volumeof blood collected during the study was expected to be approximately 72mL.

Statistical Analyses

Pharmacokinetic Analyses

Plasma concentrations and concentration-time data for dexmedetomidinewere used to calculate PK parameters; these data and results werereported separately. Details regarding the analyses of PK data weredescribed in a separate PK SAP. The separate SAP for the PK analyses wasprepared and finalized prior to database lock.

Safety Analyses

All safety analyses were performed using the Safety Population. Allsubjects who received at least one dose of study drug were included inthe population for safety analysis. Adverse events (AEs) werecharacterized by type, severity, seriousness, and relationship totreatment. Adverse events were coded by preferred term and system organclass using MedDRA version 20.0.

Efficacy Analyses

The primary efficacy endpoint of the study was the absolute change frombaseline in the PEC total score at 120 min. The intent to treatpopulation was analyzed and consist of all patients who took any studymedication and who had both baseline and at least 1 efficacy assessmentafter dosing.

Results Summary:

Demographics

The demographics and baseline characteristics is shown below in Table47.

TABLE 47 Demographics Dexmedetomidine sublingual film 180 μg 120 μgPlacebo Overall (N = 126) (N = 429) (N = 126) (N = 381) Mean age (years)46.0 (11.91) 45.7 (11.32) 45.1 (11.13) 45.6 (11.43) Female N (%) 44(34.9) 52 (40.3) 44 (34.9) 140 (36.7) Race (% white/ 38.9/61.1 44.4/55.639.7/60.3 41.0/59 % non-white) BMI 32.53 (7.8) 31.24 (7.6) 32.56 (7.4)32.10 (7.6) Diagnosis: Depressed 22% 16% 21% 20% Diagnosis: Hypomania 4% 11%  8%  8% Diagnosis: Mania 47% 46% 50% 47% Diagnosis: MixedEpisodes 24% 21% 17% 21% Diagnosis: Unspecified  3%  6%  4%  4% BaselinePEC means 18 18 17.9 NA

3. Efficacy

Dexmedetomidine sublingual film significantly improved the severity ofagitation from baseline as measured by PEC, ACES scales and CGI-Iscores. Key efficacy findings at 2 hours post-dose are presented below.

(a) Primary Efficacy Endpoint (PEC reduction): a reduction in the PECscore (PANS S or the Positive and Negative Syndrome Scale, ExcitatoryComponent) for agitation was observed with rapid calming withoutexcessive sedation at the clinical regulatory endpoint and at earliertime-points. The primary efficacy endpoint was the mean change frombaseline in PEC total score at 2 hours (120 minutes) compared toplacebo. There were 2 dose cohorts (120 μg(N=129) and 180 (N=126)) and126 placebo patients. Active patients in each of the 2 dose cohorts werecompared to placebo patients. The change from baseline in PEC at 2 hoursfor patients treated with dexmedetomidine sublingual film was comparedwith placebo using a mixed model repeated measures (MMRM) analysis, withbaseline PEC, treatment group, time, the interaction between treatmentgroups and time, and the interaction between baseline PEC and time ascovariates.

The efficacy of dexmedetomidine hydrochloride sublingual film asmeasured by PEC reduction is dose-responsive and robust. The decreasefrom baseline in PEC score in the 180 dose group showed significantresponse with a −10.4 mean change from baseline (CFB) total PEC score at2 hours post dosing compared to placebo (Table 48 and FIG. 24A and FIG.24 .B). Mean changes from baseline were −9.1 points for the 120 μgtreatment groups, compared to placebo (−5 Mean change). Additionally, asearly onset of action is an important attribute for therapy in reducingagitation, the 180 μg group showed a statistically significantseparation from placebo as early as 20 minutes post dosing (FIG. 24A andFIG. 24 .B). Further, the decrease from baseline in PEC score in the 180μg and 120 μg dose groups showed significant responses at 6 hours postdosing compared to placebo (FIG. 24B).

TABLE 48 Summary of Change from Baseline at 2 hours in PANSS- PEC TotalScore and Percent of Responders at 2 hours in the PEC Score by TreatmentGroup Dexmedetomidine Endpoint Sublingual film (120 min) N Placebo 120μg 180 μg PEC Total score 126 −5.0 −9.1 *** −10.4 *** (180 μg) Changefrom 129 129 (120 Baseline (120 μg) (LSM) Response ° 126 37% 69% 85% °Proportion achieving ≥ 40% PEC reduction; * p < 0.025; *** p < 0.0001

PEC Responder Analyses: The proportion of treatment responders, definedas those with a 40% decrease from baseline in PEC total score at 2 hourspost dose, was greatest in the 180 group (85% for 180 μg, 69% for 120μg)) as compared to placebo (37%) (TABLE 48). The durability of calmingeffects of the 180 μg dose was remarkably prolonged with a sustainedstatistically significant reduction in PEC evident after 24 hrs.

Secondary Efficacy Endpoints:

Changes in secondary efficacy measures (i.e., ACES and CGI-I scores) at2 hours post-dose were consistent with the results for PEC total scoresand were indicative of improvement in symptoms of agitation aftertreatment with dexmedetomidine sublingual film.

ACES scores: A secondary objective for this study was to evaluate theduration of calming effect of dexmedetomidine sublingual thin film drugutilizing the Agitation-Calmness Evaluation Scale (ACES) collected atpre-dose, 2 hr, and 4 hr after first dose. The ACES assessment wasconsistent with the analysis of the primary endpoint, and metstatistically significance for calming as measured by ACES at two hourscompared to placebo in 120 μg and 180 μg (120 μg; p<0.0001) and (180 μg;p<0.0001). At 2 hours after dosing, subjects in the 120 μg and 180 μgtreatment groups showed significantly greater improvements relative toplacebo in ACES scores (+ about 3.0 [p<0.0001] for 120 μg; + about 3.7[p<0.0001] for 180 μg, compared to placebo of + about 1.0. Theimprovements at 4 hours post-dose were similar (+ about 2.8 [p<0.0001]for 120 μg; + about 3.2 [p<0.0001] for 180 μg, compared to placebo of +about 1.0). (FIG. 25 ).

CGI scores: The percentage of subjects achieving CGI-I scores of 1 or 2(‘very much improved’ or ‘much improved’) at 2 hours post-dose wassignificantly higher in the 120 μg group (about 70% [p<0.0001]) and inthe 180 μg dose group (about 90% [p<0.0001]), compared with placebo(about 38%). Significant improvements were also observed at 30 minutes,1 hour, and 4 hours after dosing for both treatment groups (FIG. 26 ).

Safety and Tolerability:

Dexmedetomidine sublingual film (formulations of Example 2) was welltolerated in schizophrenia and bipolar I disorder patients and had afavourable safety profile in the treatment of subjects with agitation.An overview of subjects who experienced at least 1 treatment emergentadverse event (TEAE) by treatment group for the safety population isgiven in Tables 49.

TABLE 49 Summary of adverse events in Phase III trial (schizophrenia andbipolar I disorder patient Dexmedetomidine sublingual film 180 μg N =120 μg Placebo Event (N = 2.52) (N = 255) (N = 252) Somnolence Mild 40(15.9) 43 (16.9) 15 (6.0) Moderate 16 (6.3) 11 (4.3) 1 (0.4) DizzinessMild 13 (5.2) 7 (2.7) 2 (0.8) Moderate 2 (0.8) 3 (1.2) 0 HypotensionMild 10 (4.0) 10 (3.9) 0 Moderate 3 (1.2) 4 (1.6) 0 Orthostatic Mild 9(3.6) 7 (2.7) 1 (0.4) hypotension Moderate 4 (1.6) 0 0 Hypoaesthesiaoral 12 (4.8) 7 (2.7) 1 (0.4) Dry mouth 11 (4.4) 19 (7.5) 3 (1.2) Nausea7 (2.8) 6 (2.4) 4 (1.6) Headache 6 (2.4) 12 (4.7) 12 (4.8) Paraesthesiaoral 6 (2.4) 7 (2.7) 1 (0.4)

Conclusion: Dexmedetomidine sublingual film treatment significantlyimproved the severity of agitation from baseline as measured by PEC,CGI-I, and ACES scales in schizophrenia patients. The primary efficacyendpoint was met in 120 μg, and 180 μg treatment groups as there wassignificant improvements in PEC total scores from baseline at 2 hourspost-dose with mean changes of −9.1 and −10.4 points, respectively,versus −5.0 for placebo. Reduction in agitation was observed as early as20 minutes compared to placebo. Further, changes in secondary efficacymeasures (ie, CGI-I and ACES scores) at 2 hours post-dose wereconsistent with the results for PEC total scores and were indicative ofimprovement in symptoms of agitation after treatment withDexmedetomidine sublingual film

EXAMPLE 11

TABLE 50 Composition for a tablet formulation used for oromucosaldelivery (with muco-adhesive properties) Ingredient(s) Amount % w/vDexmedetomidine 180 μg (equivalent 0.36%  hydrochloride todexmedetomidine) Lactose Monohydrate 44.27 mg 88.54%  Hypromellose (or)2.5 mg 5.0% Hydroxy propyl cellulose (or) Polyethylene oxide (or)Xanthan gum (or) Sodium alginate Croscannellose Sodium (or) 2.5 mg 5.0%sodium starch glycollate Sucralose 0.05 mg 0.1% Magnesium Stearate 0.5mg 1.0% Tablet weight 50.0 mg 100% 

Manufacturing Process:

-   -   1. Dexmedetomidine, binder (hypromellose (or) hydroxy propyl        cellulose (or) polyethylene oxide (or) xanthan gum (or) sodium        alginate) and sucralose are dissolved or dispersed in water to        prepare a solution or dispersion.    -   2. Remaining ingredients except magnesium stearate are blended        in a suitable mixer and sifted with the help of an appropriate        sieve.    -   3. The blend obtained in step 2 is granulated using a suitable        granulator.    -   4. Granules are dried in a suitable fluid bed dryer or any other        suitable dryer and size appropriately in quadro-co-mill or        multimill.    -   5. Granules are loaded into a suitable blender such as V-blender        and lubricate with magnesium stearate.    -   6. The lubricated blend obtained in step 5 is compressed into        tablets of specific dimensions using appropriate tooling.

TABLE 51 Composition for a tablet formulation used for buccal delivery(with muco-adhesive nature) Ingredient(s) Amount % w/v Dexmedetomidine180 μg (equivalent to 0.36%  hydrochloride dexmedetomidine) Lactosemonohydrate 43.77 87.54%  Hypromellose (or) Hydroxy 5.0 mg 10.0%  propylcellulose (or) Polyethylene oxide (or) Xanthan gum (or) Sodium alginateSucralose 0.05 mg 0.1% Magnesium Stearate 0.5 mg 1.0% Talc 0.5 mg 1.0%Tablet weight 50.0 mg 100% 

Manufacturing Process:

-   -   1. Dexmedetomidine hydrochloride, binder (hypromellose (or)        hydroxy propyl cellulose (or) polyethylene oxide (or) xanthan        gum (or) sodium alginate) and sucralose are dissolved or        dispersed in water to prepare a solution or dispersion.    -   2. Remaining ingredients except magnesium stearate and talc are        blended in a suitable mixer and sifted with the help of an        appropriate sieve.    -   3. The blend obtained in step 2 is granulated using a suitable        granulator.    -   4. Granules are dried in a suitable fluid bed dryer or other        dryer and size appropriately in quadro-co-mill or multimill.    -   5. Granules are loaded into a suitable blender such as V-blender        and lubricated with magnesium stearate and talc.    -   6. The lubricated blend obtained in step 5 is compressed into        tablets of specific dimensions using appropriate tooling.

TABLE 52 Composition for Dexmedetomidine hydrochloride spray formulationfor sublingual delivery Ingredients Amount % w/v Dexmedetomidine 180 μg(equivalent to 0.18%  hydrochloride dexmedetomidine) N-Methylpyrrolidone(or) 10 μL  10% Propylene Glycol (or) Polyethylene glycol (or) GlycerineEthanol 5 μL   5% Sucralose 0.1 mg 0.1% Peppermint Oil 1 μL 1.0%Purified water q.s. 100 μL q.s. 100%

Manufacturing Process:

-   -   1. The polymer (N-methylpyrrolidone (or) propylene glycol (or)        polyethylene glycol) or glycerine is dissolved or dispersed in a        part of the total water quantity.    -   2. Dexmedetomidine hydrochloride is mixed with rest of the        excipients and the solution or dispersion obtained in step 1.    -   3. The final volume is made with water in a suitable vessel.    -   4. The resultant solution is filled into appropriate spray        canisters using appropriate tooling such as metered nozzles.

TABLE 53 Composition for Dexmedetomidine hydrochloride drops formulationfor sublingual delivery Ingredient(s) Amount % w/v Dexmedetomidine 180μg (equivalent to 0.18% hydrochloride dexmedetomidine) Povidone or 5 mg 5.0% Hypromellose or Carbopol N-Methylpyrrolidone (or) 10 μL 10.0%propylene glycol (or) polyethylene glycol (or) glycerine (or) ethanolSucralose 0.1 mg  0.1% Peppermint oil 1 μL  1.0% Purified water q.s. 100μL q.s. 100%

Manufacturing Process: Simple Mixing Process

-   -   1. The polymer (N-methylpyrrolidone (or) propylene glycol (or)        polyethylene glycol) or Glycerine is dissolved or dispersed in a        part of the total water quantity.    -   2. Dexmedetomidine hydrochloride is mixed with rest of the        excipients and the solution or dispersion obtained in step 1.    -   3. The final volume is made with water in a suitable vessel.    -   4. The resultant solution is filled into appropriate pack or        bottles.

TABLE 54 Composition for Dexmedetomidine hydrochloride gel formulationfor sublingual delivery Ingredient(s) Amount % w/v Dexmedetomidine 180μg 0.18% Carbopol or 10 mg 10.0% Hypromellose or HPC or CMCN-Methylpyrrolidone (or) 10 μL 10.0% Propylene Glycol (or) Polyethyleneglyol (or) Glycerine (or) Ethanol Sucralose 0.1 mg  0.1% Peppermint Oil1 μL  1.0% Purified water q.s. 100 μL q.s. 100%

Manufacturing Process:

-   -   1. The polymer (N-methylpyrrolidone (or) propylene glycol (or)        polyethylene glycol) or glycerine) is dissolved or dispersed in        a part of the total water quantity.    -   2. Remaining ingredients are dissolved or dispersed in other        part of the water.    -   3. Resultant solutions or dispersions of Step 1 and step 2 are        mixed and final volume is made.    -   4. The resultant mixture of step 3 is packed into appropriate        pack or containers

INCORPORATION BY REFERENCE

All references, articles, publications, patents, patent publications,and patent applications cited herein are incorporated by reference intheir entireties for all purposes. However, mention of any reference,article, publication, patent, patent publication, and patent applicationcited herein is not, and should not be taken as an acknowledgment or anyform of suggestion that they constitute valid prior art or form part ofthe common general knowledge in any country in the world.

1. A method of treating an agitation of a human subject using anoromucosal formulation of dexmedetomidine, the method comprising:administering an initial dose of the oromucosal formulation ofdexmedetomidine or a pharmaceutically acceptable salt thereof to thehuman subject, wherein the initial dose is 60 mcg, 80 mcg, 90 mcg, 120mcg, or 180 mcg of dexmedetomidine; and, after at least two hours,administering a second dose of the oromucosal formulation ofdexmedetomidine or a pharmaceutically acceptable salt thereof to thehuman subject, wherein the agitation of the human subject is persistent,and wherein the second dose is 40 mcg, 60 mcg, 80 mcg, or 90 mcg ofdexmedetomidine.
 2. The method of claim 1, wherein the initial dose is60 mcg, 80 mcg, or 90 mcg.
 3. The method of claim 1, wherein the initialdose is 120 mcg or 180 mcg.
 4. The method of claim 1, wherein the seconddose is 40 mcg, 60 mcg, or 80 mcg.
 5. The method of claim 1, wherein thesecond dose is 60 mcg or 90 mcg.
 6. The method of claim 2, wherein thesecond dose is 40 mcg, 60 mcg, or 80 mcg.
 7. The method of claim 3,wherein the second dose is 40 mcg, 60 mcg, or 80 mcg.
 8. The method ofclaim 1, wherein the second dose is 60 mcg.
 9. The method of claim 3,wherein the second dose is 60 mcg.
 10. The method of claim 1, whereinthe initial dose is 120 mcg and the second dose is 60 mcg.
 11. Themethod of claim 1, wherein the initial dose is 180 mcg and the seconddose is 90 mcg.
 12. The method of claim 1 wherein the second dose isadministered to a subject having a change in PEC score of less than orequal to 40% following the initial dose.
 13. The method of claim 1wherein the second dose is administered to a subject having asystolic/diastolic blood pressure greater than 90/60, and a heart rategreater than 60 bpm.
 14. A method of treating an agitation of a humansubject using an oromucosal formulation of dexmedetomidine, the methodcomprising: administering an initial dose of the oromucosal formulationof dexmedetomidine or a pharmaceutically acceptable salt thereof to thehuman subject, wherein the initial dose is 120 mcg of dexmedetomidine;and, after at least two hours, administering a second dose of theoromucosal formulation of dexmedetomidine or a pharmaceuticallyacceptable salt thereof to the human subject, wherein the second dose is60 mcg of dexmedetomidine.
 15. A method of treating an agitation of ahuman subject using an oromucosal formulation of dexmedetomidine, themethod comprising: administering an initial dose of the oromucosalformulation of dexmedetomidine or a pharmaceutically acceptable saltthereof to the human subject, wherein the initial dose is 180 mcg ofdexmedetomidine; and, after at least two hours, administering a seconddose of the oromucosal formulation of dexmedetomidine or apharmaceutically acceptable salt thereof to the human subject, whereinthe second dose is 90 mcg of dexmedetomidine.